Heterocyclic compounds and uses thereof

ABSTRACT

Compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including P13 kinase activity, are described herein.

This application is a continuation application of U.S. application Ser.No. 14/297,526, filed Jun. 5, 2014, which is a continuation applicationof U.S. application Ser. No. 13/552,516, filed Jul. 18, 2012, now U.S.Pat. No. 8,785,470, which claims priority to U.S. ProvisionalApplication Nos. 61/528,585, filed Aug. 29, 2011, 61/547,343, filed Oct.14, 2011, 61/562,278, filed Nov. 21, 2011, 61/595,947, filed Feb. 7,2012, and 61/645,982, filed May 11, 2012, the entireties of which areincorporated herein by reference.

BACKGROUND

The activity of cells can be regulated by external signals thatstimulate or inhibit intracellular events. The process by whichstimulatory or inhibitory signals are transmitted into and within a cellto elicit an intracellular response is referred to as signaltransduction. Over the past decades, cascades of signal transductionevents have been elucidated and found to play a central role in avariety of biological responses. Defects in various components of signaltransduction pathways have been found to account for a vast number ofdiseases, including numerous forms of cancer, inflammatory disorders,metabolic disorders, vascular and neuronal diseases (Gaestel et al.Current Medicinal Chemistry (2007) 14:2214-2234).

Kinases represent a class of important signaling molecules. Kinases cangenerally be classified into protein kinases and lipid kinases, andcertain kinases exhibit dual specificities. Protein kinases are enzymesthat phosphorylate other proteins and/or themselves (i.e.,autophosphorylation). Protein kinases can be generally classified intothree major groups based upon their substrate utilization: tyrosinekinases which predominantly phosphorylate substrates on tyrosineresidues (e.g., erb2, PDGF receptor, EGF receptor, VEGF receptor, src,abl), serine/threonine kinases which predominantly phosphorylatesubstrates on serine and/or threonine residues (e.g., mTorC1, mTorC2,ATM, ATR, DNA-PK, Akt), and dual-specificity kinases which phosphorylatesubstrates on tyrosine, serine and/or threonine residues.

Lipid kinases are enzymes that catalyze the phosphorylation of lipids.These enzymes, and the resulting phosphorylated lipids and lipid-derivedbiologically active organic molecules play a role in many differentphysiological processes, including cell proliferation, migration,adhesion, and differentiation. Certain lipid kinases are membraneassociated and they catalyze the phosphorylation of lipids contained inor associated with cell membranes. Examples of such enzymes includephosphoinositide(s) kinases (e.g., PI3-kinases, PI4-Kinases),diacylglycerol kinases, and sphingosine kinases.

The phosphoinositide 3-kinases (PI3Ks) signaling pathway is one of themost highly mutated systems in human cancers. PI3K signaling is also akey factor in many other diseases in humans. PI3K signaling is involvedin many disease states including allergic contact dermatitis, rheumatoidarthritis, osteoarthritis, inflammatory bowel diseases, chronicobstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma,disorders related to diabetic complications, and inflammatorycomplications of the cardiovascular system such as acute coronarysyndrome.

PI3Ks are members of a unique and conserved family of intracellularlipid kinases that phosphorylate the 3′-OH group onphosphatidylinositols or phosphoinositides. The PI3K family comprises 15kinases with distinct substrate specificities, expression patterns, andmodes of regulation. The class I PI3Ks (p110α, p110β, p110δ, and p110γ)are typically activated by tyrosine kinases or G-protein coupledreceptors to generate PIP3, which engages downstream effectors such asthose in the Akt/PDK1 pathway, mTOR, the Tec family kinases, and the Rhofamily GTPases. The class II and III PI3Ks play a key role inintracellular trafficking through the synthesis of PI(3)P and PI(3,4)P2.The PI3Ks are protein kinases that control cell growth (mTORC1) ormonitor genomic integrity (ATM, ATR, DNA-PK, and hSmg-1).

The delta (δ) isoform of class I PI3K has been implicated, inparticular, in a number of diseases and biological processes. PI3K-δ isexpressed primarily in hematopoietic cells including leukocytes such asT-cells, dendritic cells, neutrophils, mast cells, B-cells, andmacrophages. PI3K-δ is integrally involved in mammalian immune systemfunctions such as T-cell function, B-cell activation, mast cellactivation, dendritic cell function, and neutrophil activity. Due to itsintegral role in immune system function, PI3K-δ is also involved in anumber of diseases related to undesirable immune response such asallergic reactions, inflammatory diseases, inflammation mediatedangiogenesis, rheumatoid arthritis, and auto-immune diseases such aslupus, asthma, emphysema and other respiratory diseases. Other class IPI3K involved in immune system function includes PI3K-γ, which plays arole in leukocyte signaling and has been implicated in inflammation,rheumatoid arthritis, and autoimmune diseases such as lupus.

Unlike PI3K-δ, the beta ((3) isoform of class I PI3K appears to beubiquitously expressed. PI3K-β has been implicated primarily in varioustypes of cancer including PTEN-negative cancer (Edgar et al. CancerResearch (2010) 70(3):1164-1172), and HER2-overexpressing cancer such asbreast cancer and ovarian cancer.

SUMMARY

Described herein are compounds capable of selectively inhibiting certainisoform(s) of class I PI3K without substantially affecting the activityof the remaining isoforms of the same class. For example, non-limitingexamples of inhibitors capable of selectively inhibiting PI3K-δ and/orPI3K-γ, but without substantially affecting the activity of PI3K-β aredisclosed. Such inhibitors can be effective in ameliorating diseaseconditions associated with PI3K-δ/γ activity.

In one aspect, provided herein are compounds of Formula (I):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or a pharmaceutically acceptable form thereof,wherein

W_(b) ¹ and W_(b) ² are each independently CR⁶, S, O, N or NR¹⁴, whereinat least one of W_(b) ¹ and W_(b) ² is CR⁶, N or NR¹⁴;

W_(b) ⁵ is CR⁸, CHR⁸, or N;

p is 0, 1, 2 or 3;

B is hydrogen, alkyl, alkenyl, alkynyl, amino, heteroalkyl, cycloalkyl,heterocyclyl, aryl or heteroaryl, each of which is substituted with 0-4R²;

each R² is independently alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo,cyano, hydroxyl, nitro, phosphate, urea or carbonate;

X is absent or is —(CH(R⁹))_(z)—;

Y is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R⁹)—, —C(═O)—(CHR⁹)_(z)—,—C(═O)—, —N(R⁹)—C(═O)—, —N(R⁹)—C(═O)NH—, —N(R⁹)C(R⁹)₂—, —C(═O)—N(R⁹)₂ or—C(═O)—N(R⁹)—(CHR⁹)_(z)—;

each z is independently an integer of 1, 2, 3, or 4;

R³ is C₂₋₆alkyl, fluoro, bromo, iodo, cycloalkyl, cycloalkylalkyl, aryl,heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl,alkenyl, or alkynyl, or R³ is a heteroatom selected from N, S, and O,wherein the heteroatom has a covalent bond, either directly or through aC₁-C₆ alkyl group, to an aryl, heteroaryl or heterocyclyl, or R³ and R⁶are taken together with the carbons to which they are attached form acyclic moiety; wherein each of the above substituents can be substitutedwith 0, 1, 2, or 3 R¹³;

each R⁶ is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl,acyloxy, sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, halo,cyano, heteroaryl, aryl, hydroxyl, or nitro;

R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl, ornitro;

each R⁹ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl orheteroalkyl;

W_(d) is

A is N or CR¹⁹;

R¹⁰, R¹¹, R¹², R¹³, and R¹⁹ are independently hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, haloalkyl,cyano, hydroxyl, nitro, phosphate, urea, carbonate, oxo, or NR′R″wherein R′ and R″ are taken together with nitrogen to form a cyclicmoiety;

each R⁴ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl orheteroalkyl; and

wherein the compound of Formula (I) is not one of the followingcompounds:

In one embodiment, provided herein are compounds of Formula (I):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or a pharmaceutically acceptable form thereof,wherein

W_(b) ¹ and W_(b) ² are each independently CR⁶, S, O, N or NR¹⁴, whereinat least one of W_(b) ¹ and W_(b) ² is CR⁶, N or NR¹⁴;

W_(b) ⁵ is CR⁸, CHR⁸, or N;

p is 0, 1, 2 or 3;

B is hydrogen, alkyl, alkenyl, alkynyl, amino, heteroalkyl, cycloalkyl,heterocyclyl, aryl or heteroaryl, each of which is substituted with 0-4R²;

each R² is independently alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo,cyano, hydroxyl, nitro, phosphate, urea or carbonate;

X is absent or is —(CH(R⁹))_(z)—;

Y is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R⁹)—, —C(═O)—(CHR⁹)_(z)—,—C(═O)—, —N(R⁹)—C(═O)—, —N(R⁹)—C(═O)NH—, —N(R⁹)C(R⁹)₂—, —C(═O)—N(R⁹)₂,or —C(═O)—N(R⁹)—(CHR⁹)_(z)—;

each z is independently an integer of 1, 2, 3, or 4;

R³ is C₂₋₆alkyl, fluoro, bromo, iodo, cycloalkyl, cycloalkylalkyl, aryl,heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl,alkenyl, or alkynyl, or R³ is a heteroatom selected from N, S, and O,wherein the heteroatom has a covalent bond, either directly or through aC₁-C₆ alkyl group, to an aryl, heteroaryl or heterocyclyl, or R³ and R⁶are taken together with the carbons to which they are attached form acyclic moiety; wherein each of the above substituents can be substitutedwith 0, 1, 2, or 3 R¹³;

each R⁶ is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl,acyloxy, sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, halo,cyano, heteroaryl, aryl, hydroxyl, or nitro;

R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl, ornitro;

each R⁹ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl orheteroalkyl;

W_(d) is

A is N or CR¹⁹;

R¹⁰, R¹¹, R¹², R¹³, and R¹⁹ are independently hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, haloalkyl,cyano, hydroxyl, nitro, phosphate, urea, carbonate, oxo, or NR′R″wherein R′ and R″ are taken together with nitrogen to form a cyclicmoiety;

each R⁴ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl orheteroalkyl; and

wherein R³ is not 1-methyl-4-pyrazolyl.

In certain embodiments, the compound of Formula (I) has a structure ofFormula (II):

In some embodiments, the compound of Formula (II) has a structure ofFormula (IIa) or (IIb):

In some embodiments, the compound of Formula (II) has a structure ofFormula (IIIa) or

In certain embodiments, the compound of Formula (I) has a structure ofFormula (IV):

In some embodiments, the compound of Formula (IV) has a structure ofFormula (V):

In certain embodiments, the compound of Formula (I) has a structure ofFormula (VI):

In certain embodiments, the compound of Formula (VI) has a structure ofFormula (VII):

In certain embodiments, the compound of Formula (VI) has a structure ofFormula (VIII):

In some embodiments, the compound of Formula (VIII) has a structure ofFormula (IX):

In another aspect, provided herein are compounds of Formula (XV):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or a pharmaceutically acceptable form thereof,wherein

W_(b) ¹ and W_(b) ² are each independently CR⁶, S, O, N or NR¹⁴, whereinat least one of W_(b) ¹ and W_(b) ² is CR⁶, N or NR⁴;

p is 0, 1, 2 or 3;

B is hydrogen, alkyl, alkenyl, alkynyl, amino, heteroalkyl, cycloalkyl,heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl, arylor heteroaryl are substituted with 0-4 R²;

each R² is independently alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo,cyano, hydroxyl, nitro, phosphate, urea or carbonate;

X is absent or is —(CH(R⁹))_(z)—;

Y is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R⁹)—, —C(═O)—(CHR⁹)_(z)—,—C(═O)—, —N(R⁹)—C(═O)—, —N(R⁹)—C(═O)NH—, —N(R⁹)C(R⁹)₂—,—C(═O)—N(R⁹)_(2,) or —C(═O)—N(R⁹)—(CHR⁹)_(z)—;

each z is independently an integer of 1, 2, 3, or 4;

each R⁶ is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl,acyloxy, sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, halo,cyano, heteroaryl, aryl, hydroxyl, or nitro;

each R⁹ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl orheteroalkyl;

W_(d) is

A is N or CR¹⁹;

R¹⁰, R¹¹, R¹², R¹³, and R¹⁹ are independently hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate, oxo, or NR′R″ wherein R′and R″ are taken together with nitrogen to form a cyclic moiety;

each R¹⁴ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl orheteroalkyl;

R¹⁸ is hydrogen, alkyl, haloalkyl, halo, alkoxy, cycloalkyl,cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl,heterocyclylalkyl, alkenyl, or alkynyl, or R¹⁸ is a heteroatom selectedfrom N, S, and O, wherein the heteroatom has a covalent bond eitherdirectly or through a C₁-C₆ alkyl group to an aryl, heteroaryl orheterocyclyl, or R¹⁸ and R⁶ are taken together with the carbons to whichthey are attached form a 5- or 6-membered ring; wherein each of theabove substituents can be substituted with 0, 1, 2, or 3 R¹³; and

wherein both B and R¹⁸ are not hydrogen.

In certain embodiments, the compound of Formula (XV) has a structure ofFormula (XVI):

In some embodiments, the compound of Formula (XVI) has a structure ofFormula (XVII):

In certain embodiments, the compound of Formula (XV) has a structure ofFormula (XVIII):

In some embodiments, the compound of Formula (XVIII) has a structure ofFormula (XVIV):

In certain embodiments, the compound of Formula (XV) has a structure ofFormula (XX):

In certain embodiments, the compound of Formula (XX) has a structure ofFormula (XXI):

In another aspect, provided herein are compounds of Formula (X) or (XI):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or a pharmaceutically acceptable form thereof,wherein:

W_(b) ¹ and W_(b) ² are each independently CR⁶, S, O, N or NR¹⁴, whereinat least one of W_(b) ¹ and W_(b) ² is CR⁶, N or NR¹⁴;

each R⁶ is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl,acyloxy, sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, halo,cyano, heteroaryl, aryl, hydroxyl, or nitro;

each R⁴ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl orheteroalkyl;

R¹ is -(L)-R^(1′);

L is a bond, —S—, —N(R¹⁵)—, —C(R¹⁵)₂—, —C(═O)—, or —O—;

R^(1′) is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino,acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl,nitro, phosphate, urea, carbonate, substituted nitrogen, or NR′R″wherein R′ and R″ are taken together with nitrogen to form a cyclicmoiety;

p is 0, 1, 2 or 3;

W_(b) ⁵ is CR⁸ or N;

R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl,or nitro;

R¹⁷ is alkyl, haloalkyl, alkoxy, cycloalkyl, cycloalkylalkyl, aryl,heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl,alkenyl, or alkynyl, or R¹⁷ is a heteroatom selected from N, S, and O,wherein the heteroatom has a covalent bond either directly or through aC₁-C₆ alkyl group to an aryl, heteroaryl or heterocyclyl, or R¹⁷ and R⁶are taken together with the carbons to which they are attached form a 5-or 6-membered ring; wherein each of the above substituents can besubstituted with 0, 1, 2, or 3 R¹³;

X is absent or is —(CH(R¹⁶))_(z);

Y is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁶)—, —C(═O)—(CHR¹⁶)_(z)—,—C(═O)—, —N(R¹⁶)—C(═O)—, or —N(R¹⁶)—C(═O)NH—, —N(R¹⁶)C(R¹⁶)₂—,—C(═O)—N(R⁹)₂, or —C(═O)—N(R¹⁶)—(CHR¹⁶)_(z)—;

each z is an integer of 1, 2, 3, or 4;

each R¹⁶ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl,heteroalkyl, aryl, halo or heteroaryl;

W_(d) is

A is N or CR¹⁹; and

R¹⁰, R¹¹, R¹², R¹³, and R¹⁹ are independently hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate, oxo, or NR′R″ wherein R′and R″ are taken together with nitrogen to form a cyclic moiety.

In certain embodiments, a compound as provided herein selectivelymodulates phosphatidyl inositol-3 kinase (PI3 kinase) delta isoform. Incertain embodiments, the compound selectively inhibits the delta isoformover the beta isoform. By way of non-limiting example, the ratio ofselectivity can be greater than a factor of about 10, greater than afactor of about 50, greater than a factor of about 100, greater than afactor of about 200, greater than a factor of about 400, greater than afactor of about 600, greater than a factor of about 800, greater than afactor of about 1000, greater than a factor of about 1500, greater thana factor of about 2000, greater than a factor of about 5000, greaterthan a factor of about 10,000, or greater than a factor of about 20,000,where selectivity can be measured by IC₅₀, among other means. In certainembodiments, the PI3 kinase delta isoform IC₅₀ activity of a compound asprovided herein can be less than about 1000 nM, less than about 100 nM,less than about 10 nM, or less than about 1 nM.

In certain embodiments, provided herein is a composition (e.g., apharmaceutical composition) comprising a compound as described hereinand one or more pharmaceutically acceptable excipients. In someembodiments, provided herein is a method of inhibiting a phosphatidylinositol-3 kinase (PI3 kinase), comprising contacting the PI3 kinasewith an effective amount of a compound or pharmaceutical composition asdescribed herein. In certain embodiments, a method is provided forinhibiting a phosphatidyl inositol-3 kinase (PI3 kinase) wherein saidPI3 kinase is present in a cell. The inhibition can take place in asubject suffering from a disorder selected from cancer, bone disorder,inflammatory disease, immune disease, nervous system disease (e.g., aneuropsychiatric disorder), metabolic disease, respiratory disease,thrombosis, and cardiac disease. In certain embodiments, a secondtherapeutic agent is administered to the subject.

In certain embodiments, a method is provided of selectively inhibiting aphosphatidyl inositol-3 kinase (PI3 kinase) delta isoform over PI3kinase beta isoform wherein the inhibition takes place in a cell.Non-limiting examples of the methods provided herein can comprisecontacting PI3 kinase delta isoform with an effective amount of acompound or pharmaceutical composition as provided herein. In anembodiment, such contact can occur in a cell.

In certain embodiments, a method is provided of selectively inhibiting aphosphatidyl inositol-3 kinase (PI3 kinase) delta isoform over PI3kinase beta isoform wherein the inhibition takes place in a subjectsuffering from a disorder selected from cancer, bone disorder,inflammatory disease, immune disease, nervous system disease (e.g., aneuropsychiatric disorder), metabolic disease, respiratory disease,thrombosis, and cardiac disease, said method comprising administering aneffective amount of a compound or pharmaceutical composition to saidsubject. In certain embodiments, provided herein is a method of treatinga subject suffering from a disorder associated with phosphatidylinositol-3 kinase (PI3 kinase), said method comprising selectivelymodulating the phosphatidyl inositol-3 kinase (PI3 kinase) delta isoformover PI3 kinase beta isoform by administering an amount of a compound orpharmaceutical composition to said subject, wherein said amount issufficient for selective modulation of PI3 kinase delta isoform over PI3kinase beta isoform.

In some embodiments, provided herein is a method of making a compound asdescribed herein.

In certain embodiments, provided herein is a reaction mixture comprisinga compound as described herein.

In certain embodiments, provided herein is a kit comprising a compoundas described herein.

In some embodiments, a method is provided for treating a disease ordisorder described herein, the method comprising administering atherapeutically effective amount of a compound or pharmaceuticalcomposition described herein to a subject.

In some embodiments, a method is provided for treating a PI3K mediateddisorder in a subject, the method comprising administering atherapeutically effective amount of a compound or pharmaceuticalcomposition described herein to a subject.

In some embodiments, provided herein is a use of a compound or apharmaceutical composition described herein for the treatment of adisease or disorder described herein in a subject.

In some embodiments, provided herein is a use of a compound or apharmaceutical composition described herein for the treatment of a PI3Kmediated disorder in a subject.

In some embodiments, provided herein is a use of a compound or apharmaceutical composition described herein in the manufacture of amedicament for the treatment of a disease or disorder described hereinin a subject.

In certain embodiments, provided herein is use of a compound or apharmaceutical composition described herein in the manufacture of amedicament for the treatment of a PI3K mediated disorder in a subject.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.In case of conflict, the present application, including any definitionsherein, will control.

DETAILED DESCRIPTION

In one embodiment, provided are heterocyclyl compounds, andpharmaceutically acceptable forms, including, but not limited to, salts,hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives thereof.

In another embodiment, provided are methods of treating and/or managingvarious diseases and disorders, which comprises administering to apatient a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable form (e.g., salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof. Examples of diseases and disorders are described herein.

In another embodiment, provided are methods of preventing variousdiseases and disorders, which comprises administering to a patient inneed of such prevention a prophylactically effective amount of acompound provided herein, or a pharmaceutically acceptable form (e.g.,salts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof. Examples of diseases and disorders are describedherein.

In other embodiments, a compound provided herein, or a pharmaceuticallyacceptable form (e.g., salts, hydrates, solvates, isomers, prodrugs, andisotopically labeled derivatives) thereof, is administered incombination with another drug (“second active agent”) or treatment.Second active agents include small molecules and large molecules (e.g.,proteins and antibodies), examples of which are provided herein, as wellas stem cells. Other methods or therapies that can be used incombination with the administration of compounds provided hereininclude, but are not limited to, surgery, blood transfusions,immunotherapy, biological therapy, radiation therapy, and other non-drugbased therapies presently used to treat, prevent or manage variousdisorders described herein.

Also provided are pharmaceutical compositions (e.g., single unit dosageforms) that can be used in the methods provided herein. In oneembodiment, pharmaceutical compositions comprise a compound providedherein, or a pharmaceutically acceptable form (e.g., salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, and optionally one or more second active agents.

While specific embodiments have been discussed, the specification isillustrative only and not restrictive. Many variations of thisdisclosure will become apparent to those skilled in the art upon reviewof this specification.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this specification pertains.

As used in the specification and claims, the singular form “a”, “an” and“the” includes plural references unless the context clearly dictatesotherwise.

As used herein, “agent” or “biologically active agent” or “second activeagent” refers to a biological, pharmaceutical, or chemical compound orother moiety. Non-limiting examples include simple or complex organic orinorganic molecules, a peptide, a protein, an oligonucleotide, anantibody, an antibody derivative, an antibody fragment, a vitamin, avitamin derivative, a carbohydrate, a toxin, or a chemotherapeuticcompound, and metabolites thereof. Various compounds can be synthesized,for example, small molecules and oligomers (e.g., oligopeptides andoligonucleotides), and synthetic organic compounds based on various corestructures. In addition, various natural sources can provide compoundsfor screening, such as plant or animal extracts, and the like. A skilledartisan can readily recognize that there is no limit as to thestructural nature of the agents of this disclosure.

The term “agonist” as used herein refers to a compound or agent havingthe ability to initiate or enhance a biological function of a targetprotein or polypeptide, such as increasing the activity or expression ofthe target protein or polypeptide. Accordingly, the term “agonist” isdefined in the context of the biological role of the target protein orpolypeptide. While some agonists herein specifically interact with(e.g., bind to) the target, compounds and/or agents that initiate orenhance a biological activity of the target protein or polypeptide byinteracting with other members of the signal transduction pathway ofwhich the target polypeptide is a member are also specifically includedwithin this definition.

The terms “antagonist” and “inhibitor” are used interchangeably, andthey refer to a compound or agent having the ability to inhibit abiological function of a target protein or polypeptide, such as byinhibiting the activity or expression of the target protein orpolypeptide. Accordingly, the terms “antagonist” and “inhibitor” aredefined in the context of the biological role of the target protein orpolypeptide. While some antagonists herein specifically interact with(e.g., bind to) the target, compounds that inhibit a biological activityof the target protein or polypeptide by interacting with other membersof the signal transduction pathway of which the target protein orpolypeptide are also specifically included within this definition.Non-limiting examples of biological activity inhibited by an antagonistinclude those associated with the development, growth, or spread of atumor, or an undesired immune response as manifested in autoimmunedisease.

An “anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent”refers to any agent useful in the treatment of a neoplastic condition.One class of anti-cancer agents comprises chemotherapeutic agents.“Chemotherapy” means the administration of one or more chemotherapeuticdrugs and/or other agents to a cancer patient by various methods,including intravenous, oral, intramuscular, intraperitoneal,intravesical, subcutaneous, transdermal, buccal, or inhalation or in theform of a suppository.

The term “cell proliferation” refers to a phenomenon by which the cellnumber has changed as a result of division. This term also encompassescell growth by which the cell morphology has changed (e.g., increased insize) consistent with a proliferative signal.

The term “co-administration,” “administered in combination with,” andtheir grammatical equivalents, as used herein, encompassesadministration of two or more agents to subject so that both agentsand/or their metabolites are present in the subject at the same time.Co-administration includes simultaneous administration in separatecompositions, administration at different times in separatecompositions, or administration in a composition in which both agentsare present.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound or pharmaceutical composition describedherein that is sufficient to effect the intended application including,but not limited to, disease treatment, as illustrated below. Thetherapeutically effective amount can vary depending upon the intendedapplication (in vitro or in vivo), or the subject and disease conditionbeing treated, e.g., the weight and age of the subject, the severity ofthe disease condition, the manner of administration and the like, whichcan readily be determined by one of ordinary skill in the art. The termalso applies to a dose that will induce a particular response in targetcells, e.g., reduction of platelet adhesion and/or cell migration. Thespecific dose will vary depending on, for example, the particularcompounds chosen, the dosing regimen to be followed, whether it isadministered in combination with other agents, timing of administration,the tissue to which it is administered, and the physical delivery systemin which it is carried.

As used herein, the terms “treatment”, “treating”, “palliating” and“ameliorating” are used interchangeably herein. These terms refer to anapproach for obtaining beneficial or desired results including, but notlimited to, therapeutic benefit and/or a prophylactic benefit. Bytherapeutic benefit is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient can still be afflicted with the underlying disorder. Forprophylactic benefit, the pharmaceutical compositions can beadministered to a patient at risk of developing a particular disease, orto a patient reporting one or more of the physiological symptoms of adisease, even though a diagnosis of this disease may not have been made.

A “therapeutic effect,” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit as described above. Aprophylactic effect includes delaying or eliminating the appearance of adisease or condition, delaying or eliminating the onset of symptoms of adisease or condition, slowing, halting, or reversing the progression ofa disease or condition, or any combination thereof.

“Signal transduction” is a process during which stimulatory orinhibitory signals are transmitted into and within a cell to elicit anintracellular response. A “modulator” of a signal transduction pathwayrefers to a compound which modulates the activity of one or morecellular proteins mapped to the same specific signal transductionpathway. A modulator can augment (agonist) or suppress (antagonist) theactivity of a signaling molecule.

The term “selective inhibition” or “selectively inhibit” as applied to abiologically active agent refers to the agent's ability to selectivelyreduce the target signaling activity as compared to off-target signalingactivity, via direct or interact interaction with the target. Forexample, a compound that selectively inhibits one isoform of PI3K overanother isoform of PI3K has an activity of at least 2× against a firstisoform relative to the compound's activity against the second isoform(e.g., at least about 3×, 5×, 10×, 20×, 50×, or 100×).

“Radiation therapy” means exposing a patient, using routine methods andcompositions known to the practitioner, to radiation emitters such as,but not limited to, alpha-particle emitting radionuclides (e.g.,actinium and thorium radionuclides), low linear energy transfer (LET)radiation emitters (i.e., beta emitters), conversion electron emitters(e.g., strontium-89 and samarium-153-EDTMP), or high-energy radiation,including without limitation x-rays, gamma rays, and neutrons.

“Subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g., infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult or senior adult)) and/or otherprimates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, includingcommercially relevant mammals such as cattle, pigs, horses, sheep,goats, cats, and/or dogs; and/or birds, including commercially relevantbirds such as chickens, ducks, geese, quail, and/or turkeys.

The term “in vivo” refers to an event that takes place in a subject'sbody.

The term “in vitro” refers to an event that takes places outside of asubject's body. For example, an in vitro assay encompasses any assayconducted outside of a subject. In vitro assays encompass cell-basedassays in which cells, alive or dead, are employed. In vitro assays alsoencompass a cell-free assay in which no intact cells are employed.

As used herein, “pharmaceutically acceptable esters” include, but arenot limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkylesters of acidic groups, including, but not limited to, carboxylicacids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinicacids and boronic acids.

As used herein, “pharmaceutically acceptable enol ethers” include, butare not limited to, derivatives of formula —C═C(OR) where R can beselected from alkyl, alkenyl, alkynyl, aryl, aralkyl and cycloalkyl.Pharmaceutically acceptable enol esters include, but are not limited to,derivatives of formula —C═C(OC(O)R) where R can be selected fromhydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl and cycloalkyl.

As used herein, a “pharmaceutically acceptable form” of a disclosedcompound includes, but is not limited to, pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives of disclosed compounds. In one embodiment, a“pharmaceutically acceptable form” includes, but is not limited to,pharmaceutically acceptable salts, isomers, prodrugs and isotopicallylabeled derivatives of disclosed compounds.

In certain embodiments, the pharmaceutically acceptable form is apharmaceutically acceptable salt. As used herein, the term“pharmaceutically acceptable salt” refers to those salts which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of subjects without undue toxicity, irritation,allergic response and the like, and are commensurate with a reasonablebenefit/risk ratio. Pharmaceutically acceptable salts are well known inthe art. For example, Berge et al. describes pharmaceutically acceptablesalts in detail in J. Pharmaceutical Sciences (1977) 66:1-19.Pharmaceutically acceptable salts of the compounds provided hereininclude those derived from suitable inorganic and organic acids andbases. Examples of pharmaceutically acceptable, nontoxic acid additionsalts are salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andperchloric acid or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid or malonic acidor by using other methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate,butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. In some embodiments, organic acids from which salts can bederived include, for example, acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like.

Pharmaceutically acceptable salts derived from appropriate bases includealkali metal, alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)⁴-salts.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese,aluminum, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate. Organic bases from which salts can be derived include, forexample, primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines, basicion exchange resins, and the like, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine, andethanolamine. In some embodiments, the pharmaceutically acceptable baseaddition salt is chosen from ammonium, potassium, sodium, calcium, andmagnesium salts.

In certain embodiments, the pharmaceutically acceptable form is a“solvate” (e.g., a hydrate). As used herein, the term “solvate” refersto compounds that further include a stoichiometric or non-stoichiometricamount of solvent bound by non-covalent intermolecular forces. Thesolvate can be of a disclosed compound or a pharmaceutically acceptablesalt thereof. Where the solvent is water, the solvate is a “hydrate”.Pharmaceutically acceptable solvates and hydrates are complexes that,for example, can include 1 to about 100, or 1 to about 10, or one toabout 2, about 3 or about 4, solvent or water molecules. It will beunderstood that the term “compound” as used herein encompasses thecompound and solvates of the compound, as well as mixtures thereof.

In certain embodiments, the pharmaceutically acceptable form is aprodrug. As used herein, the term “prodrug” refers to compounds that aretransformed in vivo to yield a disclosed compound or a pharmaceuticallyacceptable form of the compound. A prodrug can be inactive whenadministered to a subject, but is converted in vivo to an activecompound, for example, by hydrolysis (e.g., hydrolysis in blood). Incertain cases, a prodrug has improved physical and/or deliveryproperties over the parent compound. Prodrugs are typically designed toenhance pharmaceutically and/or pharmacokinetically based propertiesassociated with the parent compound. The prodrug compound often offersadvantages of solubility, tissue compatibility or delayed release in amammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985),pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs isprovided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,”A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated in full byreference herein. Exemplary advantages of a prodrug can include, but arenot limited to, its physical properties, such as enhanced watersolubility for parenteral administration at physiological pH compared tothe parent compound, or it enhances absorption from the digestive tract,or it can enhance drug stability for long-term storage.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound in vivo when such prodrug isadministered to a subject. Prodrugs of an active compound, as describedherein, can be prepared by modifying functional groups present in theactive compound in such a way that the modifications are cleaved, eitherin routine manipulation or in vivo, to the parent active compound.Prodrugs include compounds wherein a hydroxy, amino or mercapto group isbonded to any group that, when the prodrug of the active compound isadministered to a subject, cleaves to form a free hydroxy, free amino orfree mercapto group, respectively. Examples of prodrugs include, but arenot limited to, acetate, formate and benzoate derivatives of an alcoholor acetamide, formamide and benzamide derivatives of an amine functionalgroup in the active compound and the like. Other examples of prodrugsinclude compounds that comprise —NO, —NO₂, —ONO, or —ONO₂ moieties.Prodrugs can typically be prepared using well-known methods, such asthose described in Burger's Medicinal Chemistry and Drug Discovery,172-178, 949-982 (Manfred E. Wolff ed., 5th ed., 1995), and Design ofProdrugs (H. Bundgaard ed., Elselvier, New York, 1985).

For example, if a disclosed compound or a pharmaceutically acceptableform of the compound contains a carboxylic acid functional group, aprodrug can comprise a pharmaceutically acceptable ester formed by thereplacement of the hydrogen atom of the acid group with a group such as(C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl havingfrom 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbonatoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

Similarly, if a disclosed compound or a pharmaceutically acceptable formof the compound contains an alcohol functional group, a prodrug can beformed by the replacement of the hydrogen atom of the alcohol group witha group such as (C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanoyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate).

If a disclosed compound or a pharmaceutically acceptable form of thecompound incorporates an amine functional group, a prodrug can be formedby the replacement of a hydrogen atom in the amine group with a groupsuch as R-carbonyl, RO-carbonyl, NRR′-carbonyl where R and R′ are eachindependently (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, benzyl, a naturalα-aminoacyl or natural α-aminoacyl-natural α-aminoacyl, —C(OH)C(O)OY¹wherein Y¹ is H, (C₁-C₆)alkyl or benzyl, —C(OY²)Y³ wherein Y² is (C₁-C₄)alkyl and Y³ is (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl ormono-N- or di-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y)Y⁵ wherein Y⁴ is H ormethyl and Y⁵ is mono-N- or di-N,N—(C₁-C₆)alkylamino, morpholino,piperidin-1-yl or pyrrolidin-1-yl.

In certain embodiments, the pharmaceutically acceptable form is anisomer. “Isomers” are different compounds that have the same molecularformula. “Stereoisomers” are isomers that differ only in the way theatoms are arranged in space. As used herein, the term “isomer” includesany and all geometric isomers and stereoisomers. For example, “isomers”include geometric double bond cis- and trans-isomers, also termed E- andZ-isomers; R- and S-enantiomers; diastereomers, (d)-isomers and(1)-isomers, racemic mixtures thereof; and other mixtures thereof, asfalling within the scope of this disclosure.

Geometric isomers can be represented by the symbol

which denotes a bond that can be a single, double or triple bond asdescribed herein. Provided herein are various geometric isomers andmixtures thereof resulting from the arrangement of substituents around acarbon-carbon double bond or arrangement of substituents around acarbocyclic ring. Substituents around a carbon-carbon double bond aredesignated as being in the “Z” or “E” configuration wherein the terms“Z” and “E” are used in accordance with IUPAC standards. Unlessotherwise specified, structures depicting double bonds encompass boththe “E” and “Z” isomers.

Substituents around a carbon-carbon double bond alternatively can bereferred to as “cis” or “trans,” where “cis” represents substituents onthe same side of the double bond and “trans” represents substituents onopposite sides of the double bond. The arrangement of substituentsaround a carbocyclic ring can also be designated as “cis” or “trans.”The term “cis” represents substituents on the same side of the plane ofthe ring, and the term “trans” represents substituents on opposite sidesof the plane of the ring. Mixtures of compounds wherein the substituentsare disposed on both the same and opposite sides of plane of the ringare designated “cis/trans.”

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A mixture of a pair of enantiomers in anyproportion can be known as a “racemic” mixture. The term “(+)” is usedto designate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. The absolute stereochemistry is specifiedaccording to the Cahn-Ingold-Prelog R-S system. When a compound is anenantiomer, the stereochemistry at each chiral carbon can be specifiedby either R or S. Resolved compounds whose absolute configuration isunknown can be designated (+) or (−) depending on the direction (dextro-or levorotatory) which they rotate plane polarized light at thewavelength of the sodium D line. Certain of the compounds describedherein contain one or more asymmetric centers and can thus give rise toenantiomers, diastereomers, and other stereoisomeric forms that can bedefined, in terms of absolute stereochemistry at each asymmetric atom,as (R)- or (S)-. The present chemical entities, pharmaceuticalcompositions and methods are meant to include all such possible isomers,including racemic mixtures, optically substantially pure forms andintermediate mixtures. Optically active (R)- and (S)-isomers can beprepared, for example, using chiral synthons or chiral reagents, orresolved using conventional techniques.

The “enantiomeric excess” or “% enantiomeric excess” of a compositioncan be calculated using the equation shown below. In the example shownbelow, a composition contains 90% of one enantiomer, e.g., the Senantiomer, and 10% of the other enantiomer, e.g., the R enantiomer.

ee=(90−10)/100=80%.

Thus, a composition containing 90% of one enantiomer and 10% of theother enantiomer is said to have an enantiomeric excess of 80%. Somecompositions described herein contain an enantiomeric excess of at leastabout 50%, about 75%, about 90%, about 95%, or about 99% of the Senantiomer. In other words, the compositions contain an enantiomericexcess of the S enantiomer over the R enantiomer. In other embodiments,some compositions described herein contain an enantiomeric excess of atleast about 50%, about 75%, about 90%, about 95%, or about 99% of the Renantiomer. In other words, the compositions contain an enantiomericexcess of the R enantiomer over the S enantiomer.

For instance, an isomer/enantiomer can, in some embodiments, be providedsubstantially free of the corresponding enantiomer, and can also bereferred to as “optically enriched,” “enantiomerically enriched,”“enantiomerically pure” and “non-racemic,” as used interchangeablyherein. These terms refer to compositions in which the percent by weightof one enantiomer is greater than the amount of that one enantiomer in acontrol mixture of the racemic composition (e.g., greater than 1:1 byweight). For example, an enantiomerically enriched preparation of the Senantiomer, means a preparation of the compound having greater thanabout 50% by weight of the S enantiomer relative to the R enantiomer,such as at least about 75% by weight, further such as at least about 80%by weight. In some embodiments, the enrichment can be much greater thanabout 80% by weight, providing a “substantially enantiomericallyenriched,” “substantially enantiomerically pure” or a “substantiallynon-racemic” preparation, which refers to preparations of compositionswhich have at least about 85% by weight of one enantiomer relative toother enantiomer, such as at least about 90% by weight, and further suchas at least about 95% by weight. In certain embodiments, the compoundprovided herein is made up of at least about 90% by weight of oneenantiomer. In other embodiments, the compound is made up of at leastabout 95%, about 98%, or about 99% by weight of one enantiomer.

In some embodiments, the compound is a racemic mixture of (S)- and(R)-isomers. In other embodiments, provided herein is a mixture ofcompounds wherein individual compounds of the mixture existpredominately in an (S)- or (R)-isomeric configuration. For example, thecompound mixture has an (S)-enantiomeric excess of greater than about55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%,about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about99.5%, or more. In other embodiments, the compound mixture has an(S)-enantiomeric excess of greater than about 55% to about 99.5%,greater than about 60% to about 99.5%, greater than about 65% to about99.5%, greater than about 70% to about 99.5%, greater than about 75% toabout 99.5%, greater than about 80% to about 99.5%, greater than about85% to about 99.5%, greater than about 90% to about 99.5%, greater thanabout 95% to about 99.5%, greater than about 96% to about 99.5%, greaterthan about 97% to about 99.5%, greater than about 98% to greater thanabout 99.5%, greater than about 99% to about 99.5%, or more.

In other embodiments, the compound mixture has an (R)-enantiomericpurity of greater than about 55%, about 60%, about 65%, about 70%, about75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%,about 98%, about 99%, about 99.5% or more. In some other embodiments,the compound mixture has an (R)-enantiomeric excess of greater thanabout 55% to about 99.5%, greater than about 60% to about 99.5%, greaterthan about 65% to about 99.5%, greater than about 70% to about 99.5%,greater than about 75% to about 99.5%, greater than about 80% to about99.5%, greater than about 85% to about 99.5%, greater than about 90% toabout 99.5%, greater than about 95% to about 99.5%, greater than about96% to about 99.5%, greater than about 97% to about 99.5%, greater thanabout 98% to greater than about 99.5%, greater than about 99% to about99.5% or more.

In other embodiments, the compound mixture contains identical chemicalentities except for their stereochemical orientations, namely (S)- or(R)-isomers. For example, if a compound provided herein has —CH(R)—unit, and R is not hydrogen, then the —CH(R)— is in an (S)- or(R)-stereochemical orientation for each of the identical chemicalentities. In some embodiments, the mixture of identical chemicalentities is a racemic mixture of (S)- and (R)-isomers. In anotherembodiment, the mixture of the identical chemical entities (except fortheir stereochemical orientations), contain predominately (S)-isomers orpredominately (R)-isomers. For example, the (S)-isomers in the mixtureof identical chemical entities are present at about 55%, about 60%,about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more,relative to the (R)-isomers. In some embodiments, the (S)-isomers in themixture of identical chemical entities are present at an(S)-enantiomeric excess of greater than about 55% to about 99.5%,greater than about 60% to about 99.5%, greater than about 65% to about99.5%, greater than about 70% to about 99.5%, greater than about 75% toabout 99.5%, greater than about 80% to about 99.5%, greater than about85% to about 99.5%, greater than about 90% to about 99.5%, greater thanabout 95% to about 99.5%, greater than about 96% to about 99.5%, greaterthan about 97% to about 99.5%, greater than about 98% to greater thanabout 99.5%, greater than about 99% to about 99.5% or more.

In another embodiment, the (R)-isomers in the mixture of identicalchemical entities (except for their stereochemical orientations), arepresent at about 55%, about 60%, about 65%, about 70%, about 75%, about80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%,about 99%, about 99.5%, or more, relative to the (S)-isomers. In someembodiments, the (R)-isomers in the mixture of identical chemicalentities (except for their stereochemical orientations), are present ata (R)-enantiomeric excess greater than about 55% to about 99.5%, greaterthan about 60% to about 99.5%, greater than about 65% to about 99.5%,greater than about 70% to about 99.5%, greater than about 75% to about99.5%, greater than about 80% to about 99.5%, greater than about 85% toabout 99.5%, greater than about 90% to about 99.5%, greater than about95% to about 99.5%, greater than about 96% to about 99.5%, greater thanabout 97% to about 99.5%, greater than about 98% to greater than about99.5%, greater than about 99% to about 99.5%, or more.

Enantiomers can be isolated from racemic mixtures by any method known tothose skilled in the art, including chiral high pressure liquidchromatography (HPLC), the formation and crystallization of chiralsalts, or prepared by asymmetric syntheses. See, for example,Enantiomers, Racemates and Resolutions (Jacques, Ed., WileyInterscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977);Stereochemistry of Carbon Compounds (E. L. Eliel, Ed., McGraw-Hill, N Y,1962); and Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).

In certain embodiments, the pharmaceutically acceptable form is atautomer. As used herein, the term “tautomer” is a type of isomer thatincludes two or more interconvertable compounds resulting from at leastone formal migration of a hydrogen atom and at least one change invalency (e.g., a single bond to a double bond, a triple bond to a singlebond, or vice versa). “Tautomerization” includes prototropic orproton-shift tautomerization, which is considered a subset of acid-basechemistry. “Prototropic tautomerization” or “proton-shifttautomerization” involves the migration of a proton accompanied bychanges in bond order. The exact ratio of the tautomers depends onseveral factors, including temperature, solvent, and pH. Wheretautomerization is possible (e.g., in solution), a chemical equilibriumof tautomers can be reached. Tautomerizations (i.e., the reactionproviding a tautomeric pair) can be catalyzed by acid or base, or canoccur without the action or presence of an external agent. Exemplarytautomerizations include, but are not limited to, keto-to-enol;amide-to-imide; lactam-to-lactim; enamine-to-imine; and enamine-to-(adifferent) enamine tautomerizations. A specific example of keto-enoltautomerization is the interconversion of pentane-2,4-dione and4-hydroxypent-3-en-2-one tautomers. Another example of tautomerizationis phenol-keto tautomerization. A specific example of phenol-ketotautomerization is the interconversion of pyridin-4-ol andpyridin-4(1H)-one tautomers.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of this disclosure.

The disclosure also embraces isotopically labeled compounds which areidentical to those recited herein, except that one or more atoms arereplaced by an atom having an atomic mass or mass number different fromthe atomic mass or mass number usually found in nature. Examples ofisotopes that can be incorporated into disclosed compounds includeisotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine andchlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F,and ³⁶Cl, respectively. Certain isotopically-labeled disclosed compounds(e.g., those labeled with ³H and ¹⁴C) are useful in compound and/orsubstrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14(i.e., ¹⁴C) isotopes can allow for ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) can afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements). Isotopically labeled disclosed compoundscan generally be prepared by substituting an isotopically labeledreagent for a non-isotopically labeled reagent. In some embodiments,provided herein are compounds that can also contain unnaturalproportions of atomic isotopes at one or more of atoms that constitutesuch compounds. All isotopic variations of the compounds as providedherein, whether radioactive or not, are encompassed within the scope ofthe present disclosure.

“Pharmaceutically acceptable carrier” or “pharmaceutically acceptableexcipient” includes any and all solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents and the like. The use of such media and agents forpharmaceutically active substances is well known in the art. Exceptinsofar as any conventional media or agent is incompatible with theactive ingredient, its use in the therapeutic compositions as providedherein is contemplated. Supplementary active ingredients can also beincorporated into the pharmaceutical compositions.

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75th ed., inside cover, and specificfunctional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in OrganicChemistry, Thomas Sorrell, University Science Books, Sausalito, 1999;Smith and March March's Advanced Organic Chemistry, 5th ed., John Wiley& Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3rd ed., Cambridge UniversityPress, Cambridge, 1987.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to ten carbon atoms (e.g., C₁-C₁₀ alkyl).Whenever it appears herein, a numerical range such as “1 to 10” refersto each integer in the given range; e.g., “1 to 10 carbon atoms” meansthat the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3carbon atoms, etc., up to and including 10 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” whereno numerical range is designated. In some embodiments, it is a C₁-C₆alkyl group. In some embodiments, alkyl groups have 1 to 10, 1 to 6, or1 to 3 carbon atoms. Representative saturated straight chain alkylsinclude, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl,-n-pentyl, and -n-hexyl; while saturated branched alkyls include, butare not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl,-isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl,4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, and the like. The alkylis attached to the parent molecule by a single bond. Unless statedotherwise in the specification, an alkyl group is optionally substitutedby one or more of substituents which independently include: acyl, alkyl,alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy,amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl,sulfonate, urea, —Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,—N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or —O—P(═O)(OR^(a))₂ where each R^(a) is independently hydrogen,alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

“Perhaloalkyl” refers to an alkyl group in which all of the hydrogenatoms have been replaced with a halogen selected from fluoro, chloro,bromo, and iodo. In some embodiments, all of the hydrogen atoms are eachreplaced with fluoro. In some embodiments, all of the hydrogen atoms areeach replaced with chloro. Examples of perhaloalkyl groups include —CF₃,—CF₂CF₃, —CF₂CF₂CF₃, —CCl₃, —CFCl₂, —CF₂Cl and the like.

“Alkyl-cycloalkyl” refers to an -(alkyl)cycloalkyl radical where alkyland cycloalkyl are as provided herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for alkyl and cycloalkyl respectively. The“alkyl-cycloalkyl” is bonded to the parent molecular structure throughthe alkyl group. The terms “alkenyl-cycloalkyl” and “alkynyl-cycloalkyl”mirror the above description of “alkyl-cycloalkyl” wherein the term“alkyl” is replaced with “alkenyl” or “alkynyl” respectively, and“alkenyl” or “alkynyl” are as described herein.

“Alkylaryl” refers to an -(alkyl)aryl radical where aryl and alkyl areas provided herein and which are optionally substituted by one or moreof the substituents described as suitable substituents for aryl andalkyl respectively. The “alkylaryl” is bonded to the parent molecularstructure through the alkyl group. The terms “-(alkenyl)aryl” and“-(alkynyl)aryl” mirror the above description of “-(alkyl)aryl” whereinthe term “alkyl” is replaced with “alkenyl” or “alkynyl” respectively,and “alkenyl” or “alkynyl” are as described herein.

“Alkyl-heteroaryl” refers to an -(alkyl)heteroaryl radical whereheteroaryl and alkyl are as provided herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroaryl and alkyl respectively. The“alkyl-heteroaryl” is bonded to the parent molecular structure throughthe alkyl group. The terms “-(alkenyl)heteroaryl” and“-(alkynyl)heteroaryl” mirror the above description of“-(alkyl)heteroaryl” wherein the term “alkyl” is replaced with “alkenyl”or “alkynyl” respectively, and “alkenyl” or “alkynyl” are as describedherein.

“Alkyl-heterocyclyl” refers to an -(alkyl)heterocycyl radical wherealkyl and heterocyclyl are as provided herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heterocyclyl and alkyl respectively. The“alkyl-heterocyclyl” is bonded to the parent molecular structure throughthe alkyl group. The terms “-(alkenyl)heterocyclyl” and“-(alkynyl)heterocyclyl” mirror the above description of“-(alkyl)heterocyclyl” wherein the term “alkyl” is replaced with“alkenyl” or “alkynyl” respectively, and “alkenyl” or “alkynyl” are asdescribed herein.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond, and having from two to ten carbon atoms (i.e.,C₂-C₁₀ alkenyl). Whenever it appears herein, a numerical range such as“2 to 10” refers to each integer in the given range; e.g., “2 to 10carbon atoms” means that the alkenyl group can consist of 2 carbonatoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. Incertain embodiments, an alkenyl comprises two to eight carbon atoms. Inother embodiments, an alkenyl comprises two to five carbon atoms (e.g.,C₂-C₅ alkenyl). The alkenyl is attached to the parent molecularstructure by a single bond, for example, ethenyl (i.e., vinyl),prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl,and the like. The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄) and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆) and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₈), octatrienyl (C₈) and the like. Unless stated otherwise in thespecification, an alkenyl group is optionally substituted by one or moresubstituents which independently include: acyl, alkyl, alkenyl, alkynyl,alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido,amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo,haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio,arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate,silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one triple bond, having from two to ten carbon atoms (i.e., C₂-C₁₀alkynyl). Whenever it appears herein, a numerical range such as “2 to10” refers to each integer in the given range; e.g., “2 to 10 carbonatoms” means that the alkynyl group can consist of 2 carbon atoms, 3carbon atoms, etc., up to and including 10 carbon atoms. In certainembodiments, an alkynyl comprises two to eight carbon atoms. In otherembodiments, an alkynyl has two to five carbon atoms (e.g., C₂-C₅alkynyl). The alkynyl is attached to the parent molecular structure by asingle bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl,and the like. Unless stated otherwise in the specification, an alkynylgroup is optionally substituted by one or more substituents whichindependently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl,cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide,carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

The term “alkoxy” refers to the group —O-alkyl, including from 1 to 10carbon atoms of a straight, branched, cyclic configuration andcombinations thereof, attached to the parent molecular structure throughan oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy,cyclopropyloxy, cyclohexyloxy and the like. “Lower alkoxy” refers toalkoxy groups containing one to six carbons. In some embodiments, C₁-C₄alkoxy is an alkoxy group which encompasses both straight and branchedchain alkyls of from 1 to 4 carbon atoms. Unless stated otherwise in thespecification, an alkoxy group is optionally substituted by one or moresubstituents which independently include: acyl, alkyl, alkenyl, alkynyl,alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido,amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo,haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio,arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate,silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein. The terms“alkenoxy” and “alkynoxy” mirror the above description of “alkoxy”wherein the prefix “alk” is replaced with “alken” or “alkyn”respectively, and the parent “alkenyl” or “alkynyl” terms are asdescribed herein.

The term “alkoxycarbonyl” refers to a group of the formula(alkoxy)(C═O)— attached to the parent molecular structure through thecarbonyl carbon having from 1 to 10 carbon atoms. Thus a C₁-C₆alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atomsattached through its oxygen to a carbonyl linker. The C₁-C₆ designationdoes not include the carbonyl carbon in the atom count. “Loweralkoxycarbonyl” refers to an alkoxycarbonyl group wherein the alkylportion of the alkoxy group is a lower alkyl group. In some embodiments,C₁-C₄ alkoxy is an alkoxy group which encompasses both straight andbranched chain alkoxy groups of from 1 to 4 carbon atoms. Unless statedotherwise in the specification, an alkoxycarbonyl group is optionallysubstituted by one or more substituents which independently include:acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl,aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃—, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein. The terms“alkenoxycarbonyl” and “alkynoxycarbonyl” mirror the above descriptionof “alkoxycarbonyl” wherein the prefix “alk” is replaced with “alken” or“alkyn” respectively, and the parent “alkenyl” or “alkynyl” terms are asdescribed herein.

“Acyl” refers to R—C(O)— groups such as, but not limited to,(alkyl)-C(O)—, (alkenyl)-C(O)—, (alkynyl)-C(O)—, (aryl)-C(O)—,(cycloalkyl)-C(O)—, (heteroaryl)-C(O)—, (heteroalkyl)-C(O)—, and(heterocycloalkyl)-C(O)—, wherein the group is attached to the parentmolecular structure through the carbonyl functionality. In someembodiments, it is a C₁-C₁₀ acyl radical which refers to the totalnumber of chain or ring atoms of the, for example, alkyl, alkenyl,alkynyl, aryl, cyclohexyl, heteroaryl or heterocycloalkyl portion plusthe carbonyl carbon of acyl. For example, a C₄-acyl has three other ringor chain atoms plus carbonyl. If the R radical is heteroaryl orheterocycloalkyl, the hetero ring or chain atoms contribute to the totalnumber of chain or ring atoms. Unless stated otherwise in thespecification, the “R” of an acyloxy group can be optionally substitutedby one or more substituents which independently include: acyl, alkyl,alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy,amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl,sulfonate, urea, —Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or —O—P(═O)(OR^(a))₂ where each R^(a) is independently hydrogen,alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

“Acyloxy” refers to a R(C═O)O— radical wherein “R” can be alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl,cyclohexyl, heteroaryl or heterocycloalkyl, which are as describedherein. The acyloxy group is attached to the parent molecular structurethrough the oxygen functionality. In some embodiments, an acyloxy groupis a C₁-C₄ acyloxy radical which refers to the total number of chain orring atoms of the alkyl, alkenyl, alkynyl, aryl, cyclohexyl, heteroarylor heterocycloalkyl portion of the acyloxy group plus the carbonylcarbon of acyl, i.e., a C₄-acyloxy has three other ring or chain atomsplus carbonyl. If the R radical is heteroaryl or heterocycloalkyl, thehetero ring or chain atoms contribute to the total number of chain orring atoms. Unless stated otherwise in the specification, the “R” of anacyloxy group is optionally substituted by one or more substituentswhich independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy,alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino,imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl and each of thesemoieties can be optionally substituted as defined herein.

“Amino” or “amine” refers to a —N(R^(b))₂, —N(R^(b))R^(b)—, or—R^(b)N(R^(b))R^(b)— radical group, where each R^(b) is independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl(bonded through a chain carbon), cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocycloalkyl (bonded through a ring carbon),heterocycloalkylalkyl, heteroaryl (bonded through a ring carbon) orheteroarylalkyl, unless stated otherwise in the specification, each ofwhich moiety can itself be optionally substituted as described herein.When a —N(R^(b))₂ group has two R^(b) other than hydrogen, they can becombined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-memberedring. For example, —N(R^(b))₂ is meant to include, but not be limitedto, 1-pyrrolidinyl and 4-morpholinyl. Unless stated otherwise in thespecification, an amino group is optionally substituted by one or moresubstituents which independently include: acyl, alkyl, alkenyl, alkynyl,alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido,amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo,haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio,arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate,silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)₁R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is 1or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

The terms “amine” and “amino” also refer to N-oxides of the groups—N⁺(H)(R^(a))O⁻, and —N⁺(R^(a))(R^(a))O—, R^(a) as described above,where the N-oxide is bonded to the parent molecular structure throughthe N atom. N-oxides can be prepared by treatment of the correspondingamino group with, for example, hydrogen peroxide orm-chloroperoxybenzoic acid. The person skilled in the art is familiarwith reaction conditions for carrying out the N-oxidation.

“Amide” or “amido” refers to a chemical moiety with formula—C(O)N(R^(b))₂ or —NR^(b)C(O)R^(b), where R^(b) is independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl(bonded through a chain carbon), cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocycloalkyl (bonded through a ring carbon),heterocycloalkylalkyl, heteroaryl (bonded through a ring carbon) orheteroarylalkyl, unless stated otherwise in the specification, each ofwhich moiety can itself be optionally substituted as described herein.In some embodiments, this radical is a C₁-C₄ amido or amide radical,which includes the amide carbonyl in the total number of carbons in theradical. When a —C(O)N(R^(b))₂ has two R^(b) other than hydrogen, theycan be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or7-membered ring. For example, N(R^(b))₂ portion of a —C(O)N(R^(b))₂radical is meant to include, but not be limited to, 1-pyrrolidinyl and4-morpholinyl. Unless stated otherwise in the specification, an amidoR^(b) group is optionally substituted by one or more substituents whichindependently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl,cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide,carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

The term “amide” or “amido” is inclusive of an amino acid or a peptidemolecule. Any amine, hydroxy, or carboxyl side chain on the compoundsdescribed herein can be transformed into an amide group. The proceduresand specific groups to make such amides are known to those of skill inthe art and can readily be found in reference sources such as Greene andWuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley &Sons, New York, N.Y., 1999, which is incorporated herein by reference inits entirety.

“Amidino” refers to both the —C(═NR^(b))N(R^(b))₂ and—N(R^(b))—C(═NR^(b))— radicals, where each R^(b) is independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl(bonded through a chain carbon), cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocycloalkyl (bonded through a ring carbon),heterocycloalkylalkyl, heteroaryl (bonded through a ring carbon) orheteroarylalkyl, unless stated otherwise in the specification, each ofwhich moiety can itself be optionally substituted as described herein.

“Aromatic” or “aryl” refers to a radical with six to ten ring atoms(e.g., C₆-C₁₀ aromatic or C₆-C₁₀ aryl) which has at least one ringhaving a conjugated pi electron system which is carbocyclic (e.g.,phenyl, fluorenyl, and naphthyl). For example, bivalent radicals formedfrom substituted benzene derivatives and having the free valences atring atoms are named as substituted phenylene radicals. In otherembodiments, bivalent radicals derived from univalent polycyclichydrocarbon radicals whose names end in “-yl” by removal of one hydrogenatom from the carbon atom with the free valence are named by adding“-idene” to the name of the corresponding univalent radical, e.g., anaphthyl group with two points of attachment is termed naphthylidene.Whenever it appears herein, a numerical range such as “6 to 10 aryl”refers to each integer in the given range; e.g., “6 to 10 ring atoms”means that the aryl group can consist of 6 ring atoms, 7 ring atoms,etc., up to and including 10 ring atoms. The term includes monocyclic orfused-ring polycyclic (i.e., rings which share adjacent pairs of ringatoms) groups. Unless stated otherwise in the specification, an arylmoiety can be optionally substituted by one or more substituents whichindependently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl,cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide,carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

“Aralkyl” or “arylalkyl” refers to an (aryl)alkyl-radical where aryl andalkyl are as provided herein and which are optionally substituted by oneor more of the substituents described as suitable substituents for aryland alkyl respectively. The “aralkyl/arylalkyl” is bonded to the parentmolecular structure through the alkyl group. The terms“aralkenyl/arylalkenyl” and “aralkynyl/arylalkynyl” mirror the abovedescription of “aralkyl/arylalkyl” wherein the “alkyl” is replaced with“alkenyl” or “alkynyl” respectively, and the “alkenyl” or “alkynyl”terms are as described herein.

“Azide” refers to a —N₃ radical.

“Carbamate” refers to any of the following radicals: —O—(C═O)—N(R^(b))—,—O—(C═O)—N(R^(b))₂, —N(R^(b))—(C═O)—O—, and —N(R^(b))—(C═O)—OR^(b),wherein each R^(b) is independently selected from alkyl, alkenyl,alkynyl, haloalkyl, heteroalkyl (bonded through a chain carbon),cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bondedthrough a ring carbon), heterocycloalkylalkyl, heteroaryl (bondedthrough a ring carbon) or heteroarylalkyl, unless stated otherwise inthe specification, each of which moiety can itself be optionallysubstituted as described herein.

“Carbonate” refers to a —O—(C═O)—O— radical.

“Carbonyl” refers to a —(C═O)— radical.

“Carboxaldehyde” refers to a —(C═O)H radical.

“Carboxyl” refers to a —(C═O)OH radical.

“Cyano” refers to a —CN radical.

“Cycloalkyl” and “carbocyclyl” each refer to a monocyclic or polycyclicradical that contains only carbon and hydrogen, and can be saturated orpartially unsaturated. Partially unsaturated cycloalkyl groups can betermed “cycloalkenyl” if the carbocycle contains at least one doublebond, or “cycloalkynyl” if the carbocycle contains at least one triplebond. Cycloalkyl groups include groups having from 3 to 10 ring atoms(i.e., C₃-C₁₀ cycloalkyl). Whenever it appears herein, a numerical rangesuch as “3 to 10” refers to each integer in the given range; e.g., “3 to10 carbon atoms” means that the cycloalkyl group can consist of 3 carbonatoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 10carbon atoms. The term “cycloalkyl” also includes bridged andspiro-fused cyclic structures containing no heteroatoms. The term alsoincludes monocyclic or fused-ring polycyclic (i.e., rings which shareadjacent pairs of ring atoms) groups. In some embodiments, it is a C₃-C₈cycloalkyl radical. In some embodiments, it is a C₃-C₅ cycloalkylradical. Illustrative examples of cycloalkyl groups include, but are notlimited to the following moieties: C₃₋₆ carbocyclyl groups include,without limitation, cyclopropyl (C₃), cyclobutyl (C₄), cyclopentyl (C₅),cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl(C₆) and the like. Examples of C₃₋₈ carbocyclyl groups include theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈),bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and the like. Examples ofC₃₋₁₀ carbocyclyl groups include the aforementioned C₃₋₈ carbocyclylgroups as well as octahydro-1H-indenyl, decahydronaphthalenyl,spiro[4.5]decanyl and the like. Unless stated otherwise in thespecification, a cycloalkyl group is optionally substituted by one ormore substituents which independently include: acyl, alkyl, alkenyl,alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino,amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl,sulfonate, urea, —Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or —O—P(═O)(OR^(a))₂ where each R^(a) is independently hydrogen,alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

“Cycloalkyl-alkyl” refers to a -(cycloalkyl)alkyl radical wherecycloalkyl and alkyl are as provided herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for cycloalkyl and alkyl respectively. The“cycloalkyl-alkyl” is bonded to the parent molecular structure throughthe cycloalkyl group. The terms “cycloalkyl-alkenyl” and“cycloalkyl-alkynyl” mirror the above description of “cycloalkyl-alkyl”wherein the term “alkyl” is replaced with “alkenyl” or “alkynyl”respectively, and “alkenyl” or “alkynyl” are as described herein.

“Cycloalkyl-heterocycloalkyl” refers to a -(cycloalkyl)heterocycylalkylradical where cycloalkyl and heterocycloalkyl are as provided herein andwhich are optionally substituted by one or more of the substituentsdescribed as suitable substituents for heterocycloalkyl and cycloalkylrespectively. The “cycloalkyl-heterocycloalkyl” is bonded to the parentmolecular structure through the cycloalkyl group.

“Cycloalkyl-heteroaryl” refers to a -(cycloalkyl)heteroaryl radicalwhere cycloalkyl and heteroaryl are as provided herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroaryl and cycloalkyl respectively. The“cycloalkyl-heteroaryl” is bonded to the parent molecular structurethrough the cycloalkyl group.

As used herein, a “covalent bond” or “direct bond” refers to a singlebond joining two groups.

“Ester” refers to a radical of formula —COOR, where R is selected fromalkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded through a chaincarbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl(bonded through a ring carbon), heterocycloalkylalkyl, heteroaryl(bonded through a ring carbon) or heteroarylalkyl. Any amine, hydroxy,or carboxyl side chain on the compounds described herein can beesterified. The procedures and specific groups to make such esters areknown to those of skill in the art and can readily be found in referencesources such as Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporatedherein by reference in its entirety. Unless stated otherwise in thespecification, an ester group can be optionally substituted by one ormore substituents which independently include: acyl, alkyl, alkenyl,alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino,amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl,sulfonate, urea, —Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or —O—P(═O)(OR^(a))₂ where each R^(a) is independently hydrogen,alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

“Ether” refers to a —R^(b)—O—R^(b)— radical where each R^(b) isindependently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein.

“Halo”, “halide”, or, alternatively, “halogen” means fluoro, chloro,bromo or iodo. The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and“haloalkoxy” include alkyl, alkenyl, alkynyl and alkoxy structures thatare substituted with one or more halo groups or with combinationsthereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” includehaloalkyl and haloalkoxy groups, respectively, in which the halo isfluorine, such as, but not limited to, trifluoromethyl, difluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Eachof the alkyl, alkenyl, alkynyl and alkoxy groups are as defined hereinand can be optionally further substituted as defined herein.

“Heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” include alkyl,alkenyl and alkynyl radicals, respectively, which have one or moreskeletal chain atoms selected from an atom other than carbon, e.g.,oxygen, nitrogen, sulfur, phosphorus or combinations thereof. Anumerical range can be given, e.g., C₁-C₄ heteroalkyl which refers tothe chain length in total, which in this example is 4 atoms long. Forexample, a —CH₂OCH₂CH₃ radical is referred to as a “C₄” heteroalkyl,which includes the heteroatom center in the atom chain lengthdescription. Connection to the parent molecular structure can be througheither a heteroatom or a carbon in the heteroalkyl chain. For example,an N-containing heteroalkyl moiety refers to a group in which at leastone of the skeletal atoms is a nitrogen atom. One or more heteroatom(s)in the heteroalkyl radical can be optionally oxidized. One or morenitrogen atoms, if present, can also be optionally quaternized. Forexample, heteroalkyl also includes skeletal chains substituted with oneor more nitrogen oxide (—O—) substituents. Exemplary heteroalkyl groupsinclude, without limitation, ethers such as methoxyethanyl(—CH₂CH₂OCH₃), ethoxymethanyl (—CH₂OCH₂CH₃), (methoxymethoxy)ethanyl(—CH₂CH₂OCH₂OCH₃), (methoxymethoxy)methanyl (—CH₂OCH₂OCH₃) and(methoxyethoxy)methanyl (—CH₂OCH₂ CH₂OCH₃) and the like; amines such as—CH₂CH₂NHCH₃, —CH₂CH₂N(CH₃)₂, —CH₂NHCH₂CH₃, —CH₂N(CH₂CH₃)(CH₃) and thelike. Heteroalkyl, heteroalkenyl, and heteroalkynyl groups can each beoptionally substituted by one or more substituents which independentlyinclude: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl,aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃—, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

“Heteroalkyl-aryl” refers to a -(heteroalkyl)aryl radical whereheteroalkyl and aryl are as provided herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroalkyl and aryl respectively. The“heteroalkyl-aryl” is bonded to the parent molecular structure throughan atom of the heteroalkyl group.

“Heteroalkyl-heteroaryl” refers to a -(heteroalkyl)heteroaryl radicalwhere heteroalkyl and heteroaryl are as provided herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroalkyl and heteroaryl respectively. The“heteroalkyl-heteroaryl” is bonded to the parent molecular structurethrough an atom of the heteroalkyl group.

“Heteroalkyl-heterocycloalkyl” refers to a-(heteroalkyl)heterocycloalkyl radical where heteroalkyl andheterocycloalkyl are as provided herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroalkyl and heterocycloalkyl respectively. The“heteroalkyl-heterocycloalkyl” is bonded to the parent molecularstructure through an atom of the heteroalkyl group.

“Heteroalkyl-cycloalkyl” refers to a -(heteroalkyl)cycloalkyl radicalwhere heteroalkyl and cycloalkyl are as provided herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroalkyl and cycloalkyl respectively. The“heteroalkyl-cycloalkyl” is bonded to the parent molecular structurethrough an atom of the heteroalkyl group.

“Heteroaryl” or, alternatively, “heteroaromatic” refers to a refers to aradical of a 5-18 membered monocyclic or polycyclic (e.g., bicyclic ortricyclic) aromatic ring system (e.g., having 6, 10 or 14 π electronsshared in a cyclic array) having ring carbon atoms and 1-6 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen, phosphorousand sulfur (“5-18 membered heteroaryl”). Heteroaryl polycyclic ringsystems can include one or more heteroatoms in one or both rings.Whenever it appears herein, a numerical range such as “5 to 18” refersto each integer in the given range; e.g., “5 to 18 ring atoms” meansthat the heteroaryl group can consist of 5 ring atoms, 6 ring atoms,etc., up to and including 18 ring atoms. For example, bivalent radicalsderived from univalent heteroaryl radicals whose names end in “-yl” byremoval of one hydrogen atom from the atom with the free valence arenamed by adding “-idene” to the name of the corresponding univalentradical, e.g., a pyridyl group with two points of attachment is apyridylidene.

For example, an N-containing “heteroaromatic” or “heteroaryl” moietyrefers to an aromatic group in which at least one of the skeletal atomsof the ring is a nitrogen atom. One or more heteroatom(s) in theheteroaryl radical can be optionally oxidized. One or more nitrogenatoms, if present, can also be optionally quaternized. Heteroaryl alsoincludes ring systems substituted with one or more nitrogen oxide (—O—)substituents, such as pyridinyl N-oxides. The heteroaryl is attached tothe parent molecular structure through any atom of the ring(s).

“Heteroaryl” also includes ring systems wherein the heteroaryl ring, asdefined above, is fused with one or more aryl groups wherein the pointof attachment to the parent molecular structure is either on the aryl oron the heteroaryl ring, or wherein the heteroaryl ring, as definedabove, is fused with one or more cycloalkyl or heterocycyl groupswherein the point of attachment to the parent molecular structure is onthe heteroaryl ring. For polycyclic heteroaryl groups wherein one ringdoes not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl andthe like), the point of attachment to the parent molecular structure canbe on either ring, i.e., either the ring bearing a heteroatom (e.g.,2-indolyl) or the ring that does not contain a heteroatom (e.g.,5-indolyl). In some embodiments, a heteroaryl group is a 5-10 memberedaromatic ring system having ring carbon atoms and 1-4 ring heteroatomsprovided in the aromatic ring system, wherein each heteroatom isindependently selected from nitrogen, oxygen, phosphorous, and sulfur(“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group isa 5-8 membered aromatic ring system having ring carbon atoms and 1-4ring heteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen, phosphorous,and sulfur (“5-8 membered heteroaryl”). In some embodiments, aheteroaryl group is a 5-6 membered aromatic ring system having ringcarbon atoms and 1-4 ring heteroatoms provided in the aromatic ringsystem, wherein each heteroatom is independently selected from nitrogen,oxygen, phosphorous, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, phosphorous, and sulfur. In someembodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatomsselected from nitrogen, oxygen, phosphorous, and sulfur. In someembodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selectedfrom nitrogen, oxygen, phosphorous, and sulfur.

Examples of heteroaryls include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl,benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl,benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl,pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.,thienyl). Unless stated otherwise in the specification, a heteroarylmoiety is optionally substituted by one or more substituents whichindependently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl,cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide,carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl and each of thesemoieties can be optionally substituted as defined herein.

“Heteroaryl-alkyl” refers to a -(heteroalyl)alkyl radical whereheteroaryl and alkyl are as provided herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroaryl and alkyl respectively. The“heteroalyl-alkyl” is bonded to the parent molecular structure throughany atom of the heteroaryl group.

“Heteroaryl-heterocycloalkyl” refers to an -(heteroalyl)heterocycloalkylradical where heteroaryl and heterocycloalkyl are as provided herein andwhich are optionally substituted by one or more of the substituentsdescribed as suitable substituents for heteroaryl and heterocycloalkylrespectively. The “heteroaryl-heterocycloalkyl” is bonded to the parentmolecular structure through an atom of the heteroaryl group.

“Heteroaryl-cycloalkyl” refers to an -(heteroaryl)cycloalkyl radicalwhere heteroaryl and cycloalkyl are as provided herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroaryl and cycloalkyl respectively. The“heteroaryl-cycloalkyl” is bonded to the parent molecular structurethrough a carbon atom of the heteroaryl group.

“Heterocyclyl”, “heterocycloalkyl” or ‘heterocarbocyclyl” each refer toany 3- to 18-membered non-aromatic radical monocyclic or polycyclicmoiety comprising at least one heteroatom selected from nitrogen,oxygen, phosphorous and sulfur. A heterocyclyl group can be amonocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein thepolycyclic ring systems can be a fused, bridged or spiro ring system.Heterocyclyl polycyclic ring systems can include one or more heteroatomsin one or both rings. A heterocyclyl group can be saturated or partiallyunsaturated. Partially unsaturated heterocycloalkyl groups can be termed“heterocycloalkenyl” if the heterocyclyl contains at least one doublebond, or “heterocycloalkynyl” if the heterocyclyl contains at least onetriple bond. Whenever it appears herein, a numerical range such as “5 to18” refers to each integer in the given range; e.g., “5 to 18 ringatoms” means that the heterocyclyl group can consist of 5 ring atoms, 6ring atoms, etc., up to and including 18 ring atoms. For example,bivalent radicals derived from univalent heterocyclyl radicals whosenames end in “-yl” by removal of one hydrogen atom from the atom withthe free valence are named by adding “-idene” to the name of thecorresponding univalent radical, e.g., a piperidine group with twopoints of attachment is a piperidylidene.

An N-containing heterocyclyl moiety refers to an non-aromatic group inwhich at least one of the ring atoms is a nitrogen atom. Theheteroatom(s) in the heterocyclyl radical can be optionally oxidized.One or more nitrogen atoms, if present, can be optionally quaternized.Heterocyclyl also includes ring systems substituted with one or morenitrogen oxide (—O—) substituents, such as piperidinyl N-oxides. Theheterocyclyl is attached to the parent molecular structure through anyatom of any of the ring(s).

“Heterocyclyl” also includes ring systems wherein the heterocycyl ring,as defined above, is fused with one or more carbocycyl groups whereinthe point of attachment is either on the carbocycyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment to the parent molecular structure is on the heterocyclylring. In some embodiments, a heterocyclyl group is a 3-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, phosphorous and sulfur (“3-10 membered heterocyclyl”).In some embodiments, a heterocyclyl group is a 5-8 membered non-aromaticring system having ring carbon atoms and 1-4 ring heteroatoms, whereineach heteroatom is independently selected from nitrogen, oxygen,phosphorous and sulfur (“5-8 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-6 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, phosphorousand sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen,oxygen phosphorous and sulfur. In some embodiments, the 5-6 memberedheterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen,phosphorous and sulfur. In some embodiments, the 5-6 memberedheterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen,phosphorous and sulfur.

Exemplary 3-membered heterocyclyls containing 1 heteroatom include,without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-memberedheterocyclyls containing 1 heteroatom include, without limitation,azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclylscontaining 1 heteroatom include, without limitation, tetrahydrofuranyl,dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl,dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-memberedheterocyclyls containing 2 heteroatoms include, without limitation,dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-memberedheterocyclyls containing 3 heteroatoms include, without limitation,triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-memberedheterocyclyl groups containing 1 heteroatom include, without limitation,piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary6-membered heterocyclyl groups containing 2 heteroatoms include, withoutlimitation, piperazinyl, morpholinyl, dithianyl, dioxanyl, andtriazinanyl. Exemplary 7-membered heterocyclyl groups containing 1heteroatom include, without limitation, azepanyl, oxepanyl andthiepanyl. Exemplary 8-membered heterocyclyl groups containing 1heteroatom include, without limitation, azocanyl, oxecanyl andthiocanyl. Exemplary bicyclic heterocyclyl groups include, withoutlimitation, indolinyl, isoindolinyl, dihydrobenzofuranyl,dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl,tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl,octahydroisochromenyl, decahydronaphthyridinyl,decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl,phthalimidyl, naphthalimidyl, chromanyl, chromenyl,1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl,5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl,5,7-dihydro-4H-thieno[2,3-c]pyranyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl,4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl,4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl,4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl,1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

Unless stated otherwise, heterocyclyl moieties are optionallysubstituted by one or more substituents which independently include:acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl,aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃—, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl and each of thesemoieties can be optionally substituted as defined herein.

“Heterocyclyl-alkyl” refers to a -(heterocyclyl)alkyl radical whereheterocyclyl and alkyl are as provided herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heterocyclyl and alkyl respectively. The“heterocyclyl-alkyl” is bonded to the parent molecular structure throughany atom of the heterocyclyl group. The terms “heterocyclyl-alkenyl” and“heterocyclyl-alkynyl” mirror the above description of“heterocyclyl-alkyl” wherein the term “alkyl” is replaced with “alkenyl”or “alkynyl” respectively, and “alkenyl” or “alkynyl” are as describedherein.

“Imino” refers to the “—(C═N)—R^(b)” radical where R^(b) is selectedfrom hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon) or heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein.

“Moiety” refers to a specific segment or functional group of a molecule.Chemical moieties are often recognized chemical entities embedded in orappended to a molecule.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Phosphate” refers to a —O—P(═O)(OR^(b))₂ radical, where each R^(b) isindependently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. In some embodiments, when R^(a) is hydrogen anddepending on the pH, the hydrogen can be replaced by an appropriatelycharged counter ion.

“Phosphonate” refers to a —O—P(═O)(R^(b))(OR^(b)) radical, where eachR^(b) is independently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. In some embodiments, when R^(a) is hydrogen anddepending on the pH, the hydrogen can be replaced by an appropriatelycharged counter ion.

“Phosphinate” refers to a —P(═O)(R^(b))(OR^(b)) radical, where eachR^(b) is independently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. In some embodiments, when R^(a) is hydrogen anddepending on the pH, the hydrogen can be replaced by an appropriatelycharged counter ion.

A “leaving group or atom” is any group or atom that will, under thereaction conditions, cleave from the starting material, thus promotingreaction at a specified site. Suitable non-limiting examples of suchgroups unless otherwise specified include halogen atoms, mesyloxy,p-nitrobenzensulphonyloxy, trifluoromethyloxy, and tosyloxy groups.

“Protecting group” has the meaning conventionally associated with it inorganic synthesis, i.e., a group that selectively blocks one or morereactive sites in a multifunctional compound such that a chemicalreaction can be carried out selectively on another unprotected reactivesite and such that the group can readily be removed after the selectivereaction is complete. A variety of protecting groups are disclosed, forexample, in T. H. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, Third Edition, John Wiley & Sons, New York (1999),incorporated herein by reference in its entirety. For example, a hydroxyprotected form is where at least one of the hydroxy groups present in acompound is protected with a hydroxy protecting group. Likewise, aminesand other reactive groups can similarly be protected.

As used herein, the terms “substituted” or “substitution” mean that atleast one hydrogen present on a group atom (e.g., a carbon or nitrogenatom) is replaced with a permissible substituent, e.g., a substituentwhich upon substitution for the hydrogen results in a stable compound,e.g., a compound which does not spontaneously undergo transformationsuch as by rearrangement, cyclization, elimination, or other reaction.Unless otherwise indicated, a “substituted” group can have a substituentat one or more substitutable positions of the group, and when more thanone position in any given structure is substituted, the substituent iseither the same or different at each position. Substituents include oneor more group(s) individually and independently selected from acyl,alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl,aryloxy, amino, amido, azide, carbonate, carbonyl, heteroalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo,haloalkoxy, haloalkyl, ester, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), —O—P(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl and each of thesemoieties can be optionally substituted as defined herein. For example, acycloalkyl substituent can have a halide substituted at one or more ringcarbons, and the like. The protecting groups that can form theprotective derivatives of the above substituents are known to those ofskill in the art and can be found in references such as Greene and Wuts,above.

“Silyl” refers to a —Si(R^(b))₃ radical where each R^(b) isindependently selected from alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein.

“Sulfanyl”, “sulfide”, and “thio” each refer to the radical —S—R^(b),wherein R^(b) is selected from alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. For instance, an “alkylthio” refers to the“alkyl-S—” radical, and “arylthio” refers to the “aryl-S—” radical, eachof which are bound to the parent molecular group through the S atom. Theterms “sulfide”, “thiol”, “mercapto”, and “mercaptan” can also eachrefer to the group —R^(b)SH.

“Sulfinyl” or “sulfoxide” refers to the —S(O)—R^(b) radical, wherein for“sulfinyl”, R^(b) is H and for “sulfoxide”, R^(b) is selected fromalkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded through a chaincarbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl(bonded through a ring carbon), heterocycloalkylalkyl, heteroaryl(bonded through a ring carbon) or heteroarylalkyl, unless statedotherwise in the specification, each of which moiety can itself beoptionally substituted as described herein.

“Sulfonyl” or “sulfone” refers to the —S(O₂)—R^(b) radical, whereinR^(b) is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein.

“Sulfonamidyl” or “sulfonamido” refers to the following radicals:—S(═O)₂—N(R^(b))₂, —N(R^(b))—S(═O)₂—R^(b), —S(═O)₂—N(R^(b))—, or—N(R^(b))—S(═O)₂—, where each R^(b) is independently selected fromhydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon) or heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein. The R^(b) groups in—S(═O)₂—N(R^(b))₂ can be taken together with the nitrogen to which theyare attached to form a 4-, 5-, 6-, or 7-membered heterocyclyl ring. Insome embodiments, the term designates a C₁-C₄ sulfonamido, wherein eachR^(b) in the sulfonamido contains 1 carbon, 2 carbons, 3 carbons, or 4carbons total.

“Sulfoxyl” or “sulfoxide” refers to a —S(═O)₂OH radical.

“Sulfonate” refers to a —S(═O)₂—OR^(b) radical, wherein R^(b) isselected from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon) or heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein.

“Thiocarbonyl” refers to a —(C═S)— radical.

“Urea” refers to a —N(R^(b))—(C═O)—N(R^(b))₂ or—N(R^(b))—(C═O)—N(R^(b))— radical, where each R^(b) is independentlyselected from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon) or heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

Compounds

In one aspect, provided herein are compounds of Formula (I):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or a pharmaceutically acceptable form thereof,wherein

W_(b) ¹ and W_(b) ² are each independently CR⁶, S, O, N or NR¹⁴, whereinat least one of W_(b) ¹ and W_(b) ² is CR⁶, N or NR⁴;

W_(b) ⁵ is CR⁸, CHR⁸, or N;

p is 0, 1, 2 or 3;

B is hydrogen, alkyl, alkenyl, alkynyl, amino, heteroalkyl, cycloalkyl,heterocyclyl, aryl or heteroaryl, each of which is substituted with 0-4R²;

each R² is independently alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo,cyano, hydroxyl, nitro, phosphate, urea or carbonate;

X is absent or is —(CH(R⁹))_(z)—;

Y is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R⁹)—, —C(═O)—(CHR⁹)_(z)—,—C(═O)—, —N(R⁹)—C(═O)—, —N(R⁹)—C(═O)NH—, —N(R⁹)C(R⁹)₂—, —C(═O)—N(R⁹)₂,or —C(═O)—N(R⁹)—(CHR⁹)_(z)—;

each z is independently an integer of 1, 2, 3, or 4;

R³ is C₂₋₆alkyl, fluoro, bromo, iodo, cycloalkyl, cycloalkylalkyl, aryl,heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl,alkenyl, or alkynyl, or R³ is a heteroatom selected from N, S, and O,wherein the heteroatom has a covalent bond, either directly or through aC₁-C₆ alkyl group, to an aryl, heteroaryl or heterocyclyl, or R³ and R⁶are taken together with the carbons to which they are attached form acyclic moiety; wherein each of the above substituents can be substitutedwith 0, 1, 2, or 3 R¹³;

each R⁶ is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl,acyloxy, sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, halo,cyano, heteroaryl, aryl, hydroxyl, or nitro;

R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl, ornitro;

each R⁹ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl orheteroalkyl;

W_(d) is

A is N or CR¹⁹;

R¹⁰, R¹¹, R¹², R¹³, and R¹⁹ are independently hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, haloalkyl,cyano, hydroxyl, nitro, phosphate, urea, carbonate, oxo, or NR′R″wherein R′ and R″ are taken together with nitrogen to form a cyclicmoiety;

each R⁴ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl orheteroalkyl; and

wherein the compound of Formula (I) is not one of the followingcompounds:

In some embodiments, when R³ is 1-methyl-4-pyrazolyl, B is not phenylsubstituted with 0 occurrences of R¹³ or cyclopropyl substituted with 0occurrences of R¹³.

In one embodiment, provided herein are compounds of Formula (I):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or a pharmaceutically acceptable form thereof,wherein

W_(b) ¹ and W_(b) ² are each independently CR⁶, S, O, N or NR⁴, whereinat least one of W_(b) ¹ and W_(b) ² is CR⁶, N or NR¹⁴;

W_(b) ⁵ is CR⁸, CHR⁸, or N;

p is 0, 1, 2 or 3;

B is hydrogen, alkyl, alkenyl, alkynyl, amino, heteroalkyl, cycloalkyl,heterocyclyl, aryl or heteroaryl, each of which is substituted with 0-4R²;

each R² is independently alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo,cyano, hydroxyl, nitro, phosphate, urea or carbonate;

X is absent or is —(CH(R⁹))_(z)—;

Y is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R⁹)—, —C(═O)—(CHR⁹)_(z)—,—C(═O)—, —N(R⁹)—C(═O)—, —N(R⁹)—C(═O)NH—, —N(R⁹)C(R⁹)₂—, —C(═O)—N(R⁹)₂,or —C(═O)—N(R⁹)—(CHR⁹)_(z)—;

each z is independently an integer of 1, 2, 3, or 4;

R³ is C₂₋₆alkyl, fluoro, bromo, iodo, cycloalkyl, cycloalkylalkyl, aryl,heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl,alkenyl, or alkynyl, or R³ is a heteroatom selected from N, S, and O,wherein the heteroatom has a covalent bond, either directly or through aC₁-C₆ alkyl group, to an aryl, heteroaryl or heterocyclyl, or R³ and R⁶are taken together with the carbons to which they are attached form acyclic moiety; wherein each of the above substituents can be substitutedwith 0, 1, 2, or 3 R¹³;

each R⁶ is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl,acyloxy, sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, halo,cyano, heteroaryl, aryl, hydroxyl, or nitro;

R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl, ornitro;

each R⁹ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl orheteroalkyl;

W_(d) is

A is N or CR¹⁹;

R¹⁰, R¹¹, R¹², R¹³, and R¹⁹ are independently hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, haloalkyl,cyano, hydroxyl, nitro, phosphate, urea, carbonate, oxo, or NR′R″wherein R′ and R″ are taken together with nitrogen to form a cyclicmoiety;

each R¹⁴ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl orheteroalkyl; and

wherein R³ is not 1-methyl-4-pyrazolyl.

In certain embodiments, W_(b) ¹ is CR⁶. In some embodiments, W_(b) ¹ isN. In some embodiments, W_(b) ¹ is S. In some embodiments, W_(b) ¹ is O.

In certain embodiments, W_(b) ² is CR⁶. In some embodiments, W_(b) ² isN. In some embodiments, W_(b) ² is S. In some embodiments, W_(b) ² is O.

In some embodiments, W_(b) ¹ and W_(b) ² are CR⁶. In some embodiments,W_(b) ¹ is S and W_(b) ² is CR⁶. In some embodiments, W_(b) ¹ is S andW_(b) ² is N.

In certain embodiments, R⁸ is hydrogen.

In certain embodiments, each R⁶ is independently hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, fluoroalkyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl, sulfoxide,sulfone, sulfonamido, halo, cyano, heteroaryl, aryl, hydroxyl, or nitro.In some embodiments, each R⁶ is independently hydrogen, alkyl,cycloalkyl, heterocyclyl, fluoroalkyl, alkoxy, halo, cyano, heteroarylor aryl. In some embodiments, R⁶ is hydrogen, alkyl, fluoroalkyl, alkoxyor aryl. In some embodiments, each R⁶ is hydrogen.

In certain embodiments, p is 0 or 1. In certain embodiments, p is 0. Insome embodiments, p is 1.

In certain embodiments, the compound of Formula (I) has a structure ofFormula (II):

In some embodiments, the compound of Formula (II) has a structure ofFormula (IIa) or (IIb):

In some embodiments, the compound of Formula (I) has a structure ofFormula (III):

In some embodiments, the compound of Formula (II) has a structure ofFormula (IIIa) or (IIIb):

In some embodiments, the compound of Formula (I) has a structure ofFormula (IIIb):

wherein R³ is pyridyl substituted with 0, 1, 2, or 3 R¹³. In someembodiments, the compound of Formula (I) has a structure of Formula(IIIb), wherein R³ is pyridyl substituted with 1 or 2 R¹³, wherein eachoccurrence of R¹³ is independently C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆heterocyclyl, C₁₋₄ alkoxy, halo, C₁₋₄ haloalkyl, hydroxyl, or oxo. Insome embodiments, the compound of Formula (I) has a structure of Formula(IIIb), wherein R³ is pyridyl substituted with 1 or 2 R¹³, wherein eachoccurrence of R¹³ is independently methyl, methoxy, or oxo.

In some embodiments, X is —(CH(R⁹))_(z)—. In some embodiments, z is 1.In some embodiments, R⁹ is C₁₋₁₀ alkyl (e.g., methyl). In someembodiments, R⁹ is methyl.

In certain embodiments, Y is absent or —N(R⁹)—. In certain embodiments,Y is absent. In some embodiments, Y is —N(R⁹)—. In some embodiments, R⁹is hydrogen.

In certain embodiments, X—Y is

In certain embodiments, X—Y is (R)—CH(CH₃)—NH—.

In certain embodiments, R³ is C₂-C₆alkyl, fluoro, bromo, iodo,cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, alkenyl, or alkynyl, or R³ is aheteroatom selected from N, S, and O, wherein the heteroatom has acovalent bond either directly or through a C₁-C₆ alkyl group to an aryl,heteroaryl or heterocyclyl, or R³ and R⁶ are taken together with thecarbons to which they are attached form a 5- or 6-membered ring; whereineach of the above substituents can be substituted with 0, 1, 2, or 3R¹³.

In certain embodiments, R³ is cycloalkyl, cycloalkylalkyl, aryl,heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl,alkenyl, or alkynyl, or R³ is a heteroatom selected from N, S, and O,wherein the heteroatom has a covalent bond either directly or through aC₁-C₆ alkyl group to an aryl, heteroaryl or heterocyclyl, or R³ and R⁶are taken together with the carbons to which they are attached form a 5-or 6-membered ring; wherein each of the above substituents can besubstituted with 0, 1, 2, or 3 R¹³

In certain embodiments, R³ is cycloalkyl, cycloalkylalkyl, aryl, 6-10membered heteroaryl, heterocyclyl, aralkyl, heteroaralkyl,heterocyclylalkyl, alkenyl, or alkynyl, or R³ is a heteroatom selectedfrom N, S, and O, wherein the heteroatom has a covalent bond eitherdirectly or through a C₁-C₆ alkyl group to an aryl, heteroaryl orheterocyclyl, or R³ and R⁶ are taken together with the carbons to whichthey are attached form a 5- or 6-membered ring; wherein each of theabove substituents can be substituted with 0, 1, 2, or 3 R¹³.

In certain embodiments, R³ is heteroaryl substituted with 0, 1, 2 or 3R¹³. In certain embodiments, R³ is 6-10 membered heteroaryl substitutedwith 0, 1, 2 or 3 R¹³. In some embodiments, R³ is 6-membered heteroarylsubstituted with 0, 1, 2 or 3 R¹³. In some embodiments, R³ is 6-memberedheteroaryl substituted with 0 R¹³ (e.g., 4-pyridazinyl). In someembodiments, R³ is 6-membered heteroaryl substituted with 1 R¹³ (e.g.,2-methoxy-5-pyrimidyl, 2-methyl-5-pyrimidyl, 5-methyl-2-pyridyl,2-methoxy-4-pyridyl, 5-methoxy-2-pyridyl or 2-methyl-4-pyridyl). In someembodiments, R³ is pyridyl substituted with 0, 1, 2 or 3 R¹³. In someembodiments, R³ is pyridyl substituted with 1 or 2 R¹³. In someembodiments, R³ is pyridyl substituted with 1 R¹³. In some embodiments,R³ is pyridyl substituted with 2 R¹³. In some embodiments, thesubstituted pyridyl is a pyridinonyl.

In some embodiments, R³ is 9-membered heteroaryl substituted with 0, 1,2 or 3 R¹³. In some embodiments, R³ is 10-membered heteroarylsubstituted with 0, 1, 2 or 3 R¹³

In certain embodiments, R³ is a fused 5/6-bicyclic heteroarylsubstituted with 0, 1, 2 or 3 R¹³. In some embodiments, R³ is a fused5/6-bicyclic heteroaryl substituted with 0 R¹³ (e.g.,5-1H-pyrrolo[2,3-b]pyridine). In some embodiments, R³ is fused6/6-bicyclic heteroaryl substituted with 0, 1, 2 or 3 R¹³. In someembodiments, R³ is fused 6/6-bicyclic heteroaryl substituted with 0 R¹³(e.g., 3-quinolinyl).

In certain embodiments of a compound of the Formulas provided herein andelsewhere (e.g., Formula (I), (II), (IIa), (IIb), (IIIa), or (IIIb)),each occurrence of R¹³ is independently alkyl, cycloalkyl, heterocyclyl,alkoxy, amino, sulfonamido, halo, haloalkyl, hydroxyl, or oxo. In someembodiments, each occurrence of R¹³ is independently C₁₋₄ alkyl, C₃₋₆cycloalkyl, C₃₋₆ heterocyclyl, C₁₋₄ alkoxy, halo, C₁₋₄ haloalkyl,hydroxyl, or oxo. In some embodiments, each occurrence of R¹³ isindependently methyl, methoxy, halo, or oxo. In some embodiments, eachoccurrence of R¹³ is independently methyl, methoxy, or oxo.

In certain embodiments, —X—Y—W_(d) is selected from:

In certain embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In certain embodiments, R¹⁰ is hydrogen. In some embodiments, R¹⁰ isamino.

In certain embodiments, R¹¹ is haloalkyl (e.g., trifluoromethyl). Insome embodiments, R¹¹ is cyano. In some embodiments, R¹¹ is amido.

In certain embodiments, R¹² is hydrogen. In some embodiments, R¹² isamino.

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, A is N. In other embodiments, A is CR¹⁹, whereinR¹⁹ is hydrogen, alkyl, haloalkyl, arylalkyl, heterocyclyl, heteroaryl,heteroalkyl, amido, amino, halo, hydroxyl, alkoxy, or cyano. In someembodiments, R¹⁹ is hydrogen, alkyl, haloalkyl, halo, amido, amino orcyano.

In certain embodiments, when R³ is methyl, B is not phenyl orcyclopropyl substituted with 0 occurrences of R¹³.

In certain embodiments, when R³ is 1-methyl-4-pyrazolyl, B is not phenylor cyclopropyl substituted with 0 occurrences of R¹³.

In certain embodiments, when R³ is chloro, R¹¹ is not hydrogen, methylor trifluoromethyl.

In certain embodiments, R³ is methyl and R¹ is cyano. In someembodiments, R³ is chloro and R¹ is cyano.

In some embodiments, R₁₀ is hydrogen and R₁₂ is —NH₂.

In some embodiments of the compound of Formula (I), at least one of R¹⁰,R¹¹ and R¹² is hydrogen, cyano, halo, unsubstituted or substitutedalkyl, unsubstituted or substituted alkynyl, or unsubstituted orsubstituted alkenyl. In some embodiments, at least one of R¹⁰, R¹¹ andR¹² is unsubstituted or substituted aryl. In some embodiments, at leastone of R¹⁰, R¹¹ and R¹² is unsubstituted or substituted heteroaryl,which includes, but is not limited to, heteroaryl having a five memberedring, heteroaryl having a six membered ring, heteroaryl with at leastone nitrogen ring atom, heteroaryl with two nitrogen ring atoms,monocylic heteroaryl, and bicylic heteroaryl. In some embodiments, atleast one of R¹⁰, R¹¹ and R¹² is unsubstituted or substitutedheterocyclyl, which includes, but is not limited to, heterocyclyl withone nitrogen ring atom, heterocyclyl with one oxygen ring atom,heterocyclyl with one sulfur ring atom, 5 membered heterocyclyl, 6membered heterocyclyl, saturated heterocyclyl, unsaturated heterocyclyl,heterocyclyl having an unsaturated moiety connected to the heterocyclylring, heterocyclyl substituted by oxo, and heterocyclyl substituted bytwo oxo. In some embodiments, at least one of R¹⁰, R¹¹ and R¹² isunsubstituted or substituted cycloalkyl, including, but not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkyl, each ofwhich can be substituted by one oxo, and cycloalkyl having anunsaturated moiety connected to the cycloalkyl ring. In someembodiments, at least one of R¹⁰, R¹¹ and R¹² is unsubstituted orsubstituted amido, unsubstituted or substituted acyloxy, unsubstitutedor substituted alkoxycarbonyl, unsubstituted or substituted acyl, orunsubstituted or substituted sulfonamido.

In some embodiments, when at least one of R¹⁰, R¹¹ and R¹² is alkyl,alkynyl, alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkoxycarbonyl, amido, acyloxy, acyl, or sulfonamido, it is substitutedwith one or more of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy,alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl or nitro, each ofwhich alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,or sulfonamido can itself be substituted.

In some embodiments, B is alkyl, heteroalkyl, cycloalkyl, heterocyclyl,aryl, or heteroaryl, each of which is substituted with 0-4 R². Incertain embodiments, B is aryl (e.g., 6-membered aryl) substituted with0-4 occurrences of R². In some embodiments, B is phenyl substituted with0-4 occurrences of R². In some embodiments, B is phenyl substituted with0 occurrences of R². In some embodiments, B is phenyl substituted with 1occurrence of R². In some embodiments, R² is halo (e.g., fluoro).

In some embodiments, B is unsubstituted or substituted alkyl, including,but not limited to —(CH₂)₂—NR^(a)R^(a), wherein each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl, or NR^(a)R^(a) are combined together toform a cyclic moiety, which includes, but is not limited to,piperidinyl, piperazinyl, and morpholinyl. In some embodiments, B isunsubstituted or substituted amino. In some embodiments, B isunsubstituted or substituted heteroalkyl. In some embodiments, B isalkyl or cycloalkyl substituted with 0-4 occurrences or R². In someembodiments, B is isopropyl.

In some embodiments, B is selected from unsubstituted or substitutedaryl, including, but not limited to, unsubstituted or substitutedphenyl; unsubstituted or substituted heteroaryl including, but notlimited to, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl,pyrimidin-2-yl, pyrimidin-5-yl, or pyrazin-2-yl; unsubstituted orsubstituted monocyclic heteroaryl; unsubstituted or substituted bicyclicheteroaryl; a heteroaryl having two heteroatoms as ring atoms;unsubstituted or substituted heteroaryl comprising a nitrogen ring atom;unsubstituted or substituted heteroaryl having two nitrogen ring atoms;unsubstituted or substituted heteroaryl having a nitrogen and a sulfuras ring atoms; unsubstituted or substituted heterocyclyl including, butnot limited to, morpholinyl, tetrahydropyranyl, piperazinyl, andpiperidinyl; and unsubstituted or substituted cycloalkyl including, butnot limited to, cyclopentyl and cyclohexyl.

In some embodiments, B is one of the following moieties:

In some embodiments, B is unsubstituted or substituted with one or moreR² substituents. In some embodiments, R² is alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxylor nitro, each of which alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, amido, amino, acyl,acyloxy, alkoxycarbonyl or sulfonamido, can itself be substituted.

In some embodiments, R² is unsubstituted or substituted alkyl,unsubstituted or substituted heteroalkyl, unsubstituted or substitutedalkenyl, unsubstituted or substituted alkynyl, unsubstituted orsubstituted cycloalkyl, or unsubstituted or substituted heterocyclyl. Insome embodiments, R² is unsubstituted or substituted aryl, unsubstitutedor substituted arylalkyl, unsubstituted or substituted heteroaryl, orunsubstituted or substituted heteroarylalkyl. In some embodiments, R² isunsubstituted or substituted alkoxy, unsubstituted or substituted amido,or unsubstituted or substituted amino. In some embodiments, R² isunsubstituted or substituted acyl, unsubstituted or substituted acyloxy,unsubstituted or substituted alkoxycarbonyl, or unsubstituted orsubstituted sulfonamido. In some embodiments, R² is halo, selected from—I, —F, —Cl, and —Br. In some embodiments, R² is selected from cyano,hydroxyl, nitro, and a carbonate. In some embodiments, R² isunsubstituted or substituted phosphate. In some embodiments, R² isunsubstituted or substituted urea. In some embodiments, when R² isalkyl, R² is methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl,sec-butyl, pentyl, hexyl or heptyl.

In some embodiments, when R² is alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, orhydroxyl, it is substituted by phosphate, substituted by urea, orsubstituted by carbonate.

In some embodiments, when R² is alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, or sulfonamido, itis substituted by one or more of alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, amido, amino, acyl,acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl or nitro,each of which alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy,alkoxycarbonyl, or sulfonamido can itself be substituted.

In some embodiments, there are no occurrences of R². In otherembodiments, there is one occurrence of R². In still other embodiments,there are two occurrences of R². In yet other embodiments, there arethree occurrences of R². In yet other embodiments, there are fouroccurrences of R². For example, in some embodiments B is aryl orheteroaryl and there are no occurrences of R². In other instances, B isaryl or heteroaryl and there is one occurrence of R² where R² is alkylor halo.

In some embodiments, R³ is hydrogen. In some embodiments, R³ isunsubstituted or substituted alkyl, unsubstituted or substitutedalkenyl, or unsubstituted or substituted alkynyl. In some embodiments,R³ is unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted cycloalkyl, or unsubstituted orsubstituted heterocyclyl. In some embodiments, R³ is unsubstituted orsubstituted alkoxy, unsubstituted or substituted amido, or unsubstitutedor substituted amino. In some embodiments, R³ is unsubstituted orsubstituted acyl, unsubstituted or substituted acyloxy, or unsubstitutedor substituted sulfonamido. In some embodiments, R³ is halo, selectedfrom —I, —F, —Cl, and —Br. In some embodiments, R³ is H, halo, alkyl,alkoxy, heteroaryl, or cycloalkyl. For example, R³ is H, CH₃, CH₂CH₃,CF₃, Cl, or F. In some instances, R³ is CH₃, CF₃, or Cl.

In some embodiments, R³ is selected from cyano, hydroxyl, and nitro. Insome embodiments, when R³ is alkyl, R³ is methyl, ethyl, propyl,isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl or heptyl. Insome embodiments, R³ is —CF₃, —CH₂F or —CHF₂.

In some embodiments, when R³ is alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, heterocyclyl, alkoxy, amido, amino, acyl,acyloxy, or sulfonamido, it is substituted with one or more of alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,sulfonamido, halo, cyano, hydroxyl or nitro, each of which alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, orsulfonamido can itself be substituted.

In some embodiments, R³ is a 5-membered heteroaryl group. Such groupsinclude, for example, pyrrole, furan, thiophene, triazole, oxazole,pyrazole, and isoxazole. In other embodiments, R³ is a 5-memberedheterocycle, including, but not limited to, oxazoline and oxazolidinone.In still other embodiments, R³ is a 6-membered heteroaryl groupincluding, but not limited to, pyridine, pyrazine, pyrimidine andpyridazine. Alternatively, R³ is a 6-membered heterocycle, includingmoieties such as morpholino or piperidino. In other embodiments, R³ is afused 5/6-bicyclic heteroaryl, for example, benzothiazole, benzoxazole,benzisoxazole, indazole, benzimidazole, benzothiophene, indole,isoindole, purine, or pyrazolopyrimidine. In yet other embodiments, R³is a fused 5/6-bicyclic heterocycle.

In some embodiments, R³ is a C₁-C₆ alkyl group substituted with a5-membered heteroaryl, a 5-membered heterocycle, a 6-memberedheteroaryl, a 6-membered heterocycle, a fused 5/6-bicyclic heteroaryl,or a fused 5/6-bicyclic heterocycle. Alternatively, R³ is amino,sulfinyl, sulfonyl, sulfoxide, sulfone, or alkoxy where the N, S or Oheteroatom has a covalent bond either directly or through a C₁-C₆ alkylgroup to a 5-membered heteroaryl, a 5-membered heterocycle, a 6-memberedheteroaryl, a 6-membered heterocycle, a fused 5/6-bicyclic heteroaryl,or a fused 5/6-bicyclic nonaromatic heterocycle.

In other embodiments, R³ is a C₁-C₆ alkyl group substituted with a fusedpolycyclic group, wherein the polycyclic group has greater than tworings and is carbocyclic or heterocyclic; C₁-C₆ alkyl group substitutedwith a bridged cycloalkyl or bridged heterocyclic group; C₁-C₆ alkylgroup substituted with a spirocyclic cycloalkyl or spirocyclicheterocyclic group; or branched C₄-C₁₂ alkyl group, wherein saidbranched alkyl group contains at least one terminal t-butyl group.

Each of the embodiments named above for R³ is unsubstituted oroptionally additionally substituted with an alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxylor nitro group.

In certain embodiments, R³ is a substituted or unsubstitutedheterocyclyl or heteroaryl group selected from pyridine, pyrazole,piperazine, and pyrrolidine, wherein the substituent can be a C₁-C₆alkyl group or a halogen.

In some embodiments, a compound is provided wherein R³ is selected froma 5-membered heteroaryl such as a pyrrole, a furan, or a thiophenegroup; 5-membered nonaromatic heterocyclyl such as a pyrrolidine, atetrahydrofuran, or a tetrahydrothiophene group; 6-membered heteroarylsuch as pyridine, pyrazine, pyrimidine, or pyridazine; 6-memberednonaromatic heterocyclyl such as piperidine, tetrahydropyran, or thiane;and fused 5/6-bicyclic heteroaryl such as indole, isoindole, benzofuran,isobenzofuran, benzothiophene, benzimidazole, indazole, benzoxazole,benzisoxazole, or purine. In certain embodiments, R³ is a substituted orunsubstituted group such as pyridine, pyrazole, piperazine, orpyrrolidine. By way of non-limiting example, the R³ group can besubstituted with a C₁-C₆ alkyl group or a halogen. For example, the R³group can be substituted with a methyl group.

In some embodiments, a compound is provided wherein R³ is selected from

wherein R is H, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo, and haloalkyl. Incertain embodiments, R is methyl. In other embodiments, a compound isprovided wherein R³ is selected from:

In some embodiments, X is absent. In some embodiments, X is—(CH(R⁹)_()z), and z is an integer of 1, 2, 3 or 4.

In some embodiments, R⁹ is unsubstituted or substituted alkyl including,but not limited to unsubstituted or substituted C₁-C₁₀alkyl. In someembodiments, R⁹ is unsubstituted or substituted cycloalkyl including,but not limited to unsubstituted or substituted C₃-C₇ cycloalkyl. Insome embodiments, R⁹ is ethyl, methyl or hydrogen. In some embodiments,R⁹ is unsubstituted or substituted heterocyclyl including, but notlimited to, unsubstituted or substituted C₂-C₁₀heteroalkyl. In someembodiments, R⁹ is unsubstituted or substituted heteroalkyl including,but not limited to, unsubstituted or substituted C₂-C₁₀heteroalkyl.

Also provided herein is a compound of Formula (I) wherein R⁹ ishydrogen, and X is —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CH₃)—, or—CH(CH₂CH₃)—. In other embodiments, X is —(CH(R⁹))_(z), R⁹ is nothydrogen, and z is an integer of 1. When X is —CH(R⁹)— and R⁹ is nothydrogen, then the compound can adopt either an (S)- or(R)-stereochemical configuration with respect to the CH carbon. In someembodiments, the compound is a racemic mixture of (S)- and (R) isomerswith respect to the CH carbon. In other embodiments, provided herein isa mixture of compounds of Formula (I), wherein individual compounds ofthe mixture exist predominately in an (S)- or (R)-isomericconfiguration. For example, the compound mixture has an (S)-enantiomericexcess of greater than about 55%, about 60%, about 65%, about 70%, about75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%,about 98%, about 99%, about 99.5%, or more at the X carbon. In otherembodiments, the compound mixture has an (S)-enantiomeric excess ofgreater than about 55% to about 99.5%, greater than about about 60% toabout 99.5%, greater than about 65% to about 99.5%, greater than about70% to about 99.5%, greater than about 75% to about 99.5%, greater thanabout 80% to about 99.5%, greater than about 85% to about 99.5%, greaterthan about 90% to about 99.5%, greater than about 95% to about 99.5%,greater than about 96% to about 99.5%, greater than about 97% to about99.5%, greater than about 98% to greater than about 99.5%, greater thanabout 99% to about 99.5%, or more.

In other embodiments, the compound mixture has an (R)-enantiomericexcess of greater than about 55%, about 60%, about 65%, about 70%, about75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%,about 98%, about 99%, about 99.5%, or more at the CH carbon. In someother embodiments, the compound mixture has an (R)-enantiomeric excessof greater than about 55% to about 99.5%, greater than about about 60%to about 99.5%, greater than about 65% to about 99.5%, greater thanabout 70% to about 99.5%, greater than about 75% to about 99.5%, greaterthan about 80% to about 99.5%, greater than about 85% to about 99.5%,greater than about 90% to about 99.5%, greater than about 95% to about99.5%, greater than about 96% to about 99.5%, greater than about 97% toabout 99.5%, greater than about 98% to greater than about 99.5%, greaterthan about 99% to about 99.5%, or more.

In some embodiments of the compound of Formula (I), X is —CH(R⁹)—, R⁹ ismethyl or ethyl, and the compound is the (S)-isomer.

In some embodiments of the compound of Formula (I), Y is absent.

In some embodiments, Y is —O—, —S—, —S(═O)—, —S(═O)₂—, —C(═O)—,—N(R⁹)(C═O)—, —N(R⁹)(C═O)NH—, —N(R⁹)C(R⁹)₂— (such as —N(R⁹)CH₂—,including, but not limited to, —N(CH₃)CH₂—, N(CH(CH₃)₂)CH₂— or—N(CH₂CH₃)CH₂—), —N(R⁹)—, —N(CH₃)—, —N(CH₂CH₃)—, or —N(CH(CH₃)₂)—. Insome embodiments, Y is —C(═O)—(CHR⁹)_(z)— and z is an integer of 1, 2,3, or 4.

In some embodiments, at least one of X and Y is present. In someembodiments of the compound of Formula I, —XY— is —CH₂—, —CH₂—N(CH₃),—CH₂—N(CH₂CH₃), —CH(CH₃)—NH—, (S)—CH(CH₃)—NH—, or (R)—CH(CH₃)—NH—. Inother embodiments, X—Y is —N(CH₃)_CH₂—, N(CH₂CH₃) CH₂—,—N(CH(CH₃)₂)CH₂—, or —NHCH₂—.

In certain embodiments, the compound of Formula (I) has a structure ofFormula (IV):

In some embodiments, the compound of Formula (IV) has a structure ofFormula (V):

In certain embodiments, the compound of Formula (I) has a structure ofFormula (VI):

In certain embodiments, the compound of Formula (VI) has a structure ofFormula (VII):

In certain embodiments, the compound of Formula (VI) has a structure ofFormula (VIII):

In some embodiments, the compound of Formula (VIII) has a structure ofFormula (IX):

In one aspect, B is selected from the moieties presented in Table 1.

TABLE 1 Illustrative B moieties of the compounds described herein. Sub-class # B B-1 

B-2 

B-3  —CH(CH₃)₂ B-4 

B-5 

B-6 

B-7 

B-8 

B-9 

B-10

B-11

B-12

B-13

B-14

B-15

B-16

B-17

B-18

B-19

B-20

B-21

B-22

B-23

B-24

B-25

B-26

B-27

B-28

B-29

B-30

B-31

B-32

B-33

B-34

B-35

B-36

B-37

B-38

B-39

B-40

B-41

B-42

B-43

B-44

B-45

B-46

B-47

B-48

B-49

B-50

B-51

B-52

B-53

B-54

B-55

B-56

B-57

B-58

B-59

B-60

B-61

B-62

B-63

B-64

B-65

B-66

B-67

B-68

B-69

B-70

B-71

B-72

B-73

B-74

B-75

B-76

B-77

B-78

B-79

B-80

B-81

B-82

B-83

B-84

B-85

B-86

B-87 —CH₃ B-88 —CH₂CH₃ B-89

B-90

B-91

B-92

B-93

B-94

B-95

B-96

B-97

B-98

B-99

B- 100

B- 101

B- 102

In some embodiments, provided herein are the following compounds:

In another aspect, provided herein are compounds of Formula (XV):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or a pharmaceutically acceptable form thereof,wherein

W_(b) ¹ and W_(b) ² are each independently CR⁶, S, O, N or NR¹⁴, whereinat least one of W_(b) ¹ and W_(b) ² is CR⁶, N or NR⁴;

p is 0, 1, 2 or 3;

B is hydrogen, alkyl, alkenyl, alkynyl, amino, heteroalkyl, cycloalkyl,heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl, arylor heteroaryl are substituted with 0-4 R²;

each R² is independently alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo,cyano, hydroxyl, nitro, phosphate, urea or carbonate;

X is absent or is —(CH(R⁹))_(z)—;

Y is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R⁹)—, —C(═O)—(CHR⁹)_(z)—,—C(═O)—, —N(R⁹)—C(═O)—, —N(R⁹)—C(═O)NH—, —N(R⁹)C(R⁹)₂—, —C(═O)—N(R⁹)₂,or —C(═O)—N(R⁹)—(CHR⁹)_(z)—;

each z is independently an integer of 1, 2, 3, or 4;

each R⁶ is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl,acyloxy, sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, halo,cyano, heteroaryl, aryl, hydroxyl, or nitro;

each R⁹ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl orheteroalkyl;

W_(d) is R¹²;

A is N or CR⁹;

R¹⁰, R¹¹, R², R³, and R¹⁹ are independently hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate, oxo, or NR′R″ wherein R′and R″ are taken together with nitrogen to form a cyclic moiety;

each R¹⁴ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl orheteroalkyl;

R¹⁸ is hydrogen, alkyl, haloalkyl, halo, alkoxy, cycloalkyl,cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl,heterocyclylalkyl, alkenyl, or alkynyl, or R¹⁸ is a heteroatom selectedfrom N, S, and O, wherein the heteroatom has a covalent bond eitherdirectly or through a C₁-C₆ alkyl group to an aryl, heteroaryl orheterocyclyl, or R¹⁸ and R⁶ are taken together with the carbons to whichthey are attached form a 5- or 6-membered ring; wherein each of theabove substituents can be substituted with 0, 1, 2, or 3 R¹³; and

wherein both B and R¹⁸ are not hydrogen.

In certain embodiments, W_(b) ¹ is CR⁶. In some embodiments, W_(b) ¹ isN. In some embodiments, W_(b) ¹ is S. In some embodiments, W_(b) ¹ is O.

In certain embodiments, W_(b) ² is CR⁶. In some embodiments, W_(b) ² isN. In some embodiments, W_(b) ² is S. In some embodiments, W_(b) ² is O.

In some embodiments, W_(b) ¹ and W_(b) ² are CR⁶. In some embodiments,W_(b) ¹ is S and W_(b) ² is CR⁶.

In some embodiments, W_(b) ¹ is S and W_(b) ² is N.

In certain embodiments, p is 0. In some embodiments, p is 1.

In certain embodiments, R¹⁸ is hydrogen, alkyl, halo, alkoxy,cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclylalkyl, alkenyl, or alkynyl, or R¹⁸ is aheteroatom selected from N, S, and O, wherein the heteroatom has acovalent bond either directly or through a C₁-C₆ alkyl group to an aryl,heteroaryl or heterocyclyl, or R¹⁸ and R⁶ are taken together with thecarbons to which they are attached form a 5- or 6-membered ring; whereineach of the above substituents can be substituted with 0, 1, 2, or 3R¹³.

In some embodiments of the compound of Formula (XV), at least one ofR¹⁰, R¹¹ and R¹² is hydrogen, cyano, halo, unsubstituted or substitutedalkyl, unsubstituted or substituted alkynyl, or unsubstituted orsubstituted alkenyl. In some embodiments, at least one of R¹⁰, R¹¹ andR¹² is unsubstituted or substituted aryl. In some embodiments, at leastone of R¹⁰, R¹¹ and R¹² is unsubstituted or substituted heteroaryl,which includes, but is not limited to, heteroaryl having a 5 memberedring, heteroaryl having a six membered ring, heteroaryl with at leastone nitrogen ring atom, heteroaryl with two nitrogen ring atoms,monocylic heteroaryl, and bicylic heteroaryl. In some embodiments, atleast one of R¹⁰, R¹¹ and R¹² is unsubstituted or substitutedheterocyclyl, which includes, but is not limited to, heterocyclyl withone nitrogen ring atom, heterocyclyl with one oxygen ring atom,heterocyclyl with one sulfur ring atom, 5 membered heterocyclyl, 6membered heterocyclyl, saturated heterocyclyl, unsaturated heterocyclyl,heterocyclyl having an unsaturated moiety connected to the heterocyclylring, heterocyclyl substituted by oxo, and heterocyclyl substituted bytwo oxo. In some embodiments, at least one of R¹⁰, R¹¹ and R¹² isunsubstituted or substituted cycloalkyl, including, but not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkyl, each ofwhich can be substituted by one oxo, and cycloalkyl having anunsaturated moiety connected to the cycloalkyl ring. In someembodiments, at least one of R¹⁰, R¹¹ and R¹² is unsubstituted orsubstituted amido, unsubstituted or substituted acyloxy, unsubstitutedor substituted alkoxycarbonyl, unsubstituted or substituted acyl, orunsubstituted or substituted sulfonamido.

In some embodiments, when at least one of R¹⁰, R¹¹ and R¹² is alkyl,alkynyl, alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkoxycarbonyl, amido, acyloxy, acyl, or sulfonamido, it is substitutedwith one or more of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy,alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl or nitro, each ofwhich alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,or sulfonamido can itself be substituted.

In some embodiments, B is unsubstituted or substituted alkyl, including,but not limited to —(CH₂)₂—NR^(a)R^(a), wherein each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl, or NR^(a)R^(a) are combined together toform a cyclic moiety, which includes but is not limited to piperidinyl,piperazinyl, and morpholinyl. In some embodiments, B is unsubstituted orsubstituted amino. In some embodiments, B is unsubstituted orsubstituted heteroalkyl.

In some embodiments, B is selected from unsubstituted or substitutedaryl, including, but not limited to, unsubstituted or substitutedphenyl; unsubstituted or substituted heteroalyl including, but notlimited to, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl,pyrimidin-2-yl, pyrimidin-5-yl, or pyrazin-2-yl; unsubstituted orsubstituted monocyclic heteroaryl; unsubstituted or substituted bicyclicheteroaryl; a heteroaryl having two heteroatoms as ring atoms;unsubstituted or substituted heteroaryl comprising a nitrogen ring atom;unsubstituted or substituted heteroaryl having two nitrogen ring atoms;unsubstituted or substituted heteroaryl having a nitrogen and a sulfuras ring atoms; unsubstituted or substituted heterocyclyl including, butnot limited to, morpholinyl, tetrahydropyranyl, piperazinyl, andpiperidinyl; and unsubstituted or substituted cycloalkyl including, butnot limited to, cyclopentyl and cyclohexyl.

In some embodiments, B is one of the following moieties:

In some embodiments, B is unsubstituted or substituted with one or moreR² substituents. In some embodiments, R² is alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxylor nitro, each of which alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, amido, amino, acyl,acyloxy, alkoxycarbonyl or sulfonamido, can itself be substituted.

In some embodiments, R² is unsubstituted or substituted alkyl,unsubstituted or substituted heteroalkyl, unsubstituted or substitutedalkenyl, unsubstituted or substituted alkynyl, unsubstituted orsubstituted cycloalkyl, or unsubstituted or substituted heterocyclyl. Insome embodiments, R² is unsubstituted or substituted aryl, unsubstitutedor substituted arylalkyl, unsubstituted or substituted heteroaryl, orunsubstituted or substituted heteroarylalkyl. In some embodiments, R² isunsubstituted or substituted alkoxy, unsubstituted or substituted amido,or unsubstituted or substituted amino. In some embodiments, R² isunsubstituted or substituted acyl, unsubstituted or substituted acyloxy,unsubstituted or substituted alkoxycarbonyl, or unsubstituted orsubstituted sulfonamido. In some embodiments, R² is halo, selected from—I, —F, —Cl, and —Br. In some embodiments, R² is selected from cyano,hydroxyl, nitro, and a carbonate. In some embodiments, R² isunsubstituted or substituted phosphate. In some embodiments, R² isunsubstituted or substituted urea. In some embodiments, when R² isalkyl, R² is methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl,sec-butyl, pentyl, hexyl or heptyl.

In some embodiments, when R² is alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, orhydroxyl, it is substituted by phosphate, substituted by urea, orsubstituted by carbonate.

In some embodiments, when R² is alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, or sulfonamido, itis substituted by one or more of alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, amido, amino, acyl,acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl or nitro,each of which alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy,alkoxycarbonyl, or sulfonamido can itself be substituted.

In some embodiments, there are no occurrences of R². In otherembodiments, there is one occurrence of R². In still other embodiments,there are two occurrences of R². In yet other embodiments, there arethree occurrences of R². In yet other embodiments, there are fouroccurrences of R². For example, in some embodiments B is aryl orheteroaryl and there are no occurrences of R². In other instances, B isaryl or heteroaryl and there is one occurrence of R² where R² is alkylor halo.

In some embodiments, R¹⁸ is hydrogen. In some embodiments, R¹⁸ isunsubstituted or substituted alkyl, unsubstituted or substitutedalkenyl, or unsubstituted or substituted alkynyl. In some embodiments,R¹⁸ is unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted cycloalkyl, or unsubstituted orsubstituted heterocyclyl. In some embodiments, R¹⁸ is unsubstituted orsubstituted alkoxy, unsubstituted or substituted amido, or unsubstitutedor substituted amino. In some embodiments, R¹⁸ is unsubstituted orsubstituted acyl, unsubstituted or substituted acyloxy, or unsubstitutedor substituted sulfonamido. In some embodiments, R¹⁸ is halo, selectedfrom —I, —F, —Cl, and —Br. In some embodiments, R¹⁸ is H, halo, alkyl,alkoxy, heteroaryl, or cycloalkyl. For example, R¹⁸ is H, CH₃, CH₂CH₃,CF₃, Cl, or F. In some instances, R¹⁸ is CH₃, CF₃, or Cl.

In some embodiments, R¹⁸ is selected from cyano, hydroxyl, and nitro. Insome embodiments, when R¹⁸ is alkyl, R¹⁸ is methyl, ethyl, propyl,isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl or heptyl. Insome embodiments, R¹⁸ is —CF₃, —CH₂F or —CHF₂.

In some embodiments, when R¹⁸ is alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, heterocyclyl, alkoxy, amido, amino, acyl,acyloxy, or sulfonamido, it is substituted with one or more of alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,sulfonamido, halo, cyano, hydroxyl or nitro, each of which alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, orsulfonamido can itself be substituted.

In some embodiments, R¹⁸ is a 5-membered heteroaryl group. Such groupsinclude, for example, pyrrole, furan, thiophene, triazole, oxazole,pyrazole, and isoxazole. In other embodiments, R¹⁸ is a 5-memberedheterocycle, including, but not limited to, oxazoline and oxazolidinone.In still other embodiments, R¹⁸ is a 6-membered heteroaryl groupincluding, but not limited to, pyridine, pyrazine, pyrimidine andpyridazine. Alternatively, R¹⁸ is a 6-membered heterocycle, includingmoieties such as morpholino or piperidino. In other embodiments, R¹⁸ isa fused 5/6-bicyclic heteroaryl, for example, benzothiazole,benzoxazole, benzisoxazole, indazole, benzimidazole, benzothiophene,indole, isoindole, purine, or pyrazolopyrimidine. In yet otherembodiments, R¹⁸ is a fused 5/6-bicyclic heterocycle.

In some embodiments, R¹⁸ is a C₁-C₆ alkyl group substituted with a5-membered heteroaryl, a 5-membered heterocycle, a 6-memberedheteroaryl, a 6-membered heterocycle, a fused 5/6-bicyclic heteroaryl,or a fused 5/6-bicyclic heterocycle. Alternatively, R¹⁸ is amino,sulfinyl, sulfonyl, sulfoxide, sulfone, or alkoxy where the N, S or Oheteroatom has a covalent bond either directly or through a C₁-C₆ alkylgroup to a 5-membered heteroaryl, a 5-membered heterocycle, a 6-memberedheteroaryl, a 6-membered heterocycle, a fused 5/6-bicyclic heteroaryl,or a fused 5/6-bicyclic nonaromatic heterocycle.

In other embodiments, R¹⁸ is a C₁-C₆ alkyl group substituted with afused polycyclic group, wherein the polycyclic group has greater thantwo rings and is carbocyclic or heterocyclic; C₁-C₆ alkyl groupsubstituted with a bridged cycloalkyl or bridged heterocyclic group;C₁-C₆ alkyl group substituted with a spirocyclic cycloalkyl orspirocyclic heterocyclic group; or branched C₄-C₁₂ alkyl group, whereinsaid branched alkyl group contains at least one terminal t-butyl group.

Each of the embodiments named above for R¹⁸ is unsubstituted oroptionally additionally substituted with an alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalyl, alkoxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxylor nitro group.

In certain embodiments, R¹⁸ is a substituted or unsubstitutedheterocyclyl or heteroaryl group selected from pyridine, pyrazole,piperazine, and pyrrolidine, wherein the substituent can be a C₁-C₆alkyl group or a halogen.

In some embodiments, a compound is provided wherein R¹⁸ is selected froma 5-membered heteroaryl such as a pyrrole, a furan, or a thiophenegroup; 5-membered nonaromatic heterocyclyl such as a pyrrolidine, atetrahydrofuran, or a tetrahydrothiophene group; 6-membered heteroarylsuch as pyridine, pyrazine, pyrimidine, or pyridazine; 6-memberednonaromatic heterocyclyl such as piperidine, tetrahydropyran, or thiane;and fused 5/6-bicyclic heteroaryl such as indole, isoindole, benzofuran,isobenzofuran, benzothiophene, benzimidazole, indazole, benzoxazole,benzisoxazole, or purine. In certain embodiments, R¹⁸ is a substitutedor unsubstituted group such as pyridine, pyrazole, piperazine, orpyrrolidine. By way of non-limiting example, the R¹⁸ group can besubstituted with a C₁-C₆ alkyl group or a halogen. For example, the R¹⁸group can be substituted with a methyl group.

In some embodiments, a compound is provided wherein R¹⁸ is selected from

wherein R is H, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo, and haloalkyl. Incertain embodiments, R is methyl. In other embodiments, a compound isprovided wherein R¹⁸ is selected from:

In some embodiments, X is absent. In some embodiments, X is—(CH(^(R9))_()z), and z is an integer of 1, 2, 3 or 4.

In some embodiments, R⁹ is unsubstituted or substituted alkyl including,but not limited to unsubstituted or substituted C₁-C₁₀alkyl. In someembodiments, R⁹ is unsubstituted or substituted cycloalkyl including,but not limited to unsubstituted or substituted C₃-C₇ cycloalkyl. Insome embodiments, R⁹ is ethyl, methyl or hydrogen. In some embodiments,R⁹ is unsubstituted or substituted heterocyclyl including, but notlimited to, unsubstituted or substituted C₂-C₁₀heteroalkyl. In someembodiments, R⁹ is unsubstituted or substituted heteroalkyl including,but not limited to, unsubstituted or substituted C₂-C₁₀heteroalkyl.

Also provided herein is a compound of Formula (XV) wherein R⁹ ishydrogen, and X is —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CH₃)—, or—CH(CH₂CH₃)—. In other embodiments, X is —(CH(R⁹))_(z), R⁹ is nothydrogen, and z is an integer of 1. When X is —CH(R⁹)— and R⁹ is nothydrogen, then the compound can adopt either an (S)- or(R)-stereochemical configuration with respect to the CH carbon. In someembodiments, the compound is a racemic mixture of (S)- and (R) isomerswith respect to the CH carbon. In other embodiments, provided herein isa mixture of compounds of Formula (XV) wherein individual compounds ofthe mixture exist predominately in an (S)- or (R)-isomericconfiguration. For example, the compound mixture has an (S)-enantiomericexcess of greater than about 55%, about 60%, about 65%, about 70%, about75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%,about 98%, about 99%, about 99.5%, or more at the X carbon. In otherembodiments, the compound mixture has an (S)-enantiomeric excess ofgreater than about 55% to about 99.5%, greater than about about 60% toabout 99.5%, greater than about 65% to about 99.5%, greater than about70% to about 99.5%, greater than about 75% to about 99.5%, greater thanabout 80% to about 99.5%, greater than about 85% to about 99.5%, greaterthan about 90% to about 99.5%, greater than about 95% to about 99.5%,greater than about 96% to about 99.5%, greater than about 97% to about99.5%, greater than about 98% to greater than about 99.5%, greater thanabout 99% to about 99.5%, or more.

In other embodiments, the compound mixture has an (R)-enantiomericexcess of greater than about 55%, about 60%, about 65%, about 70%, about75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%,about 98%, about 99%, about 99.5%, or more at the CH carbon. In someother embodiments, the compound mixture has an (R)-enantiomeric excessof greater than about 55% to about 99.5%, greater than about about 60%to about 99.5%, greater than about 65% to about 99.5%, greater thanabout 70% to about 99.5%, greater than about 75% to about 99.5%, greaterthan about 80% to about 99.5%, greater than about 85% to about 99.5%,greater than about 90% to about 99.5%, greater than about 95% to about99.5%, greater than about 96% to about 99.5%, greater than about 97% toabout 99.5%, greater than about 98% to greater than about 99.5%, greaterthan about 99% to about 99.5%, or more.

In some embodiments, the compound of Formula (XV), X is —CH(R⁹)—, R⁹ ismethyl or ethyl, and the compound is the (S)-isomer.

In some embodiments of the compound of Formula (XV), Y is absent.

In some embodiments, Y is —O—, —S—, —S(═O)—, —S(═O)₂—, —C(═O)—,—N(R⁹)(C═O)—, —N(R⁹)(C═O)NH—, —N(R⁹)C(R⁹)₂— (such as —N(R⁹)CH₂—,including, but not limited to, —N(CH₃)CH₂—, N(CH(CH₃)₂)CH₂— or—N(CH₂CH₃)CH₂—), —N(R⁹)—, —N(CH₃)—, —N(CH₂CH₃)—, or —N(CH(CH₃)₂)—. Insome embodiments, Y is —C(═O)—(CHR⁹)_(z)— and z is an integer of 1, 2,3, or 4.

In some embodiments, at least one of X and Y is present. In someembodiments of the compound of Formula I, —XY— is —CH₂—, —CH₂—N(CH₃),—CH₂—N(CH₂CH₃), —CH(CH₃)—NH—, (S)—CH(CH₃)—NH—, or (R)—CH(CH₃)—NH—. Inother embodiments, X—Y is —N(CH₃)_CH₂—, N(CH₂CH₃) CH₂—,—N(CH(CH₃)₂)CH₂—, or —NHCH₂—.

In certain embodiments, the compound of Formula (XV) has a structure ofFormula (XVI):

In some embodiments, the compound of Formula (XVI) has a structure ofFormula (XVII):

In some embodiments of compounds of Formula (XVI) or (XVII), B is arylsubstituted with 0-3 occurrences of R². For example, B is phenylsubstituted with 0-3 occurrences of R². In some embodiments of compoundsof Formula (XVI) or (XVII), B is unsubstituted phenyl. In otherembodiments of compounds of Formula (XVI) or (XVII), B is phenylsubstituted with 1 occurrence of R². R² is, in some instances, halo oralkyl. In other embodiments of compounds of Formula (XVI) or (XVII), Bis cycloalkyl or heterocyclyl.

In still other embodiments, the compound of Formula (XV) has a structureselected from:

In certain embodiments, the compound of Formula (XV) has a structure ofFormula (XVIII):

In some embodiments, the compound of Formula (XVIII) has a structure ofFormula (XVIV):

In certain embodiments, the compound of Formula (XV) has a structure ofFormula (XX):

In certain embodiments, the compound of Formula (XX) has a structure ofFormula (XXI):

In one aspect, B is selected from the moieties presented in Table 2.

TABLE 2 Illustrative B moieties of the compounds described herein. Sub-class # B B-1

B-2

B-3 —CH(CH₃)₂ B-4

B-5

B-6

B-7

B-8

B-9

B-10

B-11

B-12

B-13

B-14

B-15

B-16

B-17

B-18

B-19

B-20

B-21

B-22

B-23

B-24

B-25

B-26

B-27

B-28

B-29

B-30

B-31

B-32

B-33

B-34

B-35

B-36

B-37

B-38

B-39

B-40

B-41

B-42

B-43

B-44

B-45

B-46

B-47

B-48

B-49

B-50

B-51

B-52

B-53

B-54

B-55

B-56

B-57

B-58

B-59

B-60

B-61

B-62

B-63

B-64

B-65

B-66

B-67

B-68

B-69

B-70

B-71

B-72

B-73

B-74

B-75

B-76

B-77

B-78

B-79

B-80

B-81

B-82

B-83

B-84

B-85

B-86

B-87 —CH₃ B-88 —CH₂CH₃ B-89

B-90

B-91

B-92

B-93

B-94

B-95

B-96

B-97

B-98

B-99

B-100

B-101

B-102

In some embodiments, the compound of Formula (XV) is selected from thefollowing:

In another aspect, provided herein are compounds of Formula (X) or (XI):

In another aspect, provided herein are compounds of Formula (X) or (XI):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or a pharmaceutically acceptable form thereof,wherein:

W_(b) ¹ and W_(b) ² are each independently CR⁶, S, O, N or NR¹⁴, whereinat least one of W_(b) ¹ and W_(b) ² is CR⁶, N or NR¹⁴;

each R⁶ is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl,acyloxy, sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, halo,cyano, heteroaryl, aryl, hydroxyl, or nitro;

each R¹⁴ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl orheteroalkyl;

R¹ is -(L)-R¹;

L is a bond, —S—, —N(R¹⁵)—, —C(R¹⁵)₂—, —C(═O)—, or —O—;

R^(1′) is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino,acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl,nitro, phosphate, urea, carbonate, substituted nitrogen, or NR′R″wherein R′ and R″ are taken together with nitrogen to form a cyclicmoiety;

p is 0, 1, 2 or 3;

W_(b) ⁵ is CR⁸ or N;

R⁸ is alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, alkoxy, amido,amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl, or nitro;

R¹⁷ is alkyl, haloalkyl, alkoxy, cycloalkyl, cycloalkylalkyl, aryl,heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl,alkenyl, or alkynyl, or R¹⁷ is a heteroatom selected from N, S, and O,wherein the heteroatom has a covalent bond either directly or through aC₁-C₆ alkyl group to an aryl, heteroaryl or heterocyclyl, or R¹⁷ and R⁶are taken together with the carbons to which they are attached form a 5-or 6-membered ring; wherein each of the above substituents can besubstituted with 0, 1, 2, or 3 R¹³;

X is absent or is —(CH(R¹⁶))_(z);

Y is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁶)—, —C(═O)—(CHR¹⁶)_(z)—,—C(═O)—, —N(R¹⁶)—C(═O)—, or —N(R¹⁶)—C(═O)NH—, —N(R¹⁶)C(R¹⁶)₂—,—C(═O)—N(R⁹)₂, or —C(═O)—N(R¹⁶)—(CHR¹⁶)_(z);

each z is an integer of 1, 2, 3, or 4;

each R¹⁶ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl,heteroalkyl, aryl, halo or heteroaryl;

W_(d) is

A is N or CR¹⁹; and

R¹⁰, R¹¹, R¹², R¹³, and R¹⁹ are independently hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate, oxo, or NR′R″ wherein R′and R″ are taken together with nitrogen to form a cyclic moiety.

In certain embodiments, W_(b) ¹ is CR⁶ and W_(b) ² is CR⁶.

In certain embodiments, W_(b) ⁵ is CH.

In certain embodiments, L is a bond, —N(R⁵)— or —C(═O)—.

In certain embodiments, the compound of Formula (I) has a structure ofFormula (XXII):

In certain embodiments, the compound of Formula (XXII) has a structureof Formula (XXIII):

wherein:R³ is aryl or heteroaryl; andR²⁰ is amido or cyano.

In certain embodiments, R³ is phenyl, pyrazolyl, or pyridyl, and R²⁰ iscyano. In certain embodiments, R³ is substituted phenyl or substitutedpyridyl. In some embodiments, the substitutions are selected from alkyl,(e.g., methyl), heteroalkyl (e.g., CF₃), alkoxy, halo, amino, hydroxyl,cyano, aryl, heteroaryl, and sulfonamido.

In certain embodiments, the compound of Formula (XXIII) is selected fromthe following:

In certain embodiments, R³ is 2-pyridyl, 4-pyridyl, pyrazinyl,pyridazinyl, or pyrimidinyl.

In certain embodiments, the compound of Formula (XXIII) is selected fromthe following:

In certain embodiments, R³ is pyridinone.

In certain embodiments, the compound of Formula (XXIII) is selected fromthe following:

In certain embodiments, R³ is pyridyl and R²⁰ is amido. In certainembodiments, R³ is pyridyl substituted with alkoxy.

In certain embodiments, the compound of Formula (XXIII) is selected fromthe following:

In certain embodiments R³ is pyrazolyl and R²⁰ is amido.

In certain embodiments, the compound of Formula (XXII) is selected fromthe following:

In certain embodiments, the compound of Formula (XXII) has a structureof Formula (XXIV):

wherein R³ is alkynyl, aryl, heteroaryl. In certain embodiments, R³ isphenyl, triazole, or pyridyl. In some embodiments, R³ is

wherein Ra is amino, and either D is nitrogen and E is carbon, or D iscarbon and E is nitrogen.

In certain embodiments, the compound of Formula (XXIV) is selected fromthe following:

In certain embodiments, the compound of Formula (I) has a structure ofFormula (XXV):

In certain embodiments, R³ is heteroaryl;

In certain embodiments, R³ is pyrimidinyl, pyridyl, or pyridanizyl;

In certain embodiments, the compound of Formula (XXV) is selected fromthe following:

In another aspect, provided herein are compounds of Formula (XXVI):

wherein:R²¹ and R²² are each independently hydrogen, methyl, chloro, or amino;R²³ is hydrogen, alkynyl, phenyl, cyano, methylsulfonyl or nitro; andwherein when R²¹ is amino, then at least one of R²² and R²³ is not H.

In certain embodiments, the compound of Formula (XXVI) is selected fromthe following:

In another aspect, provided herein are compounds of Formula (XXVII):

wherein R²⁴ is H, alkyl, or aryl.

In certain embodiments, the compound of Formula (XXVII) is selected fromthe following:

In another aspect, provided herein are compounds of Formula (XXVIII):

wherein R²⁵ is H or substituted alkyl (e.g., alkyl substituted withamide).

In certain embodiments, the compound of Formula (XXVIII) is selectedfrom the following:

wherein R²⁶ is selected from H, alkyl, heteroalkyl, cycloalkyl,heterocyclyl, aryl or heteroaryl.

In another aspect, provided herein are compounds of Formula (XXIX):

wherein R²⁷ is aryl, heteroaryl, —CO(NR²⁸R²⁸), or —N—C(O)R²⁸, and R²⁸ isselected from H, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl orheteroaryl. In certain embodiments, R²⁷ is substituted phenyl. Incertain embodiments, R²⁷ is pyridinyl or substituted pyridinyl. Incertain embodiments, R²⁷ is substituted phenyl. In certain embodiments,R²⁷ is

wherein Z is O, S, or NH; and R²⁹ is H, alkyl, or alkoxy.

In certain embodiments, the compound of Formula (XXIX) is selected fromthe following:

In some embodiments, one or more compounds described herein bind to aPI3 kinase (e.g., bind selectively). In some embodiments, one or morecompounds described herein bind selectively to a γ or δ subtype of a PI3kinase.

In some embodiments, the IC₅₀ of a subject compound for p110α, p110β,p110γ, or p110δ is less than about 1 μM, less than about 100 nM, lessthan about 50 nM, less than about 10 nM, less than 1 nM or even lessthan about 0.5 nM. In some embodiments, the IC₅₀ of a subject compoundfor mTor is less than about 1 μM, less than about 100 nM, less thanabout 50 nM, less than about 10 nM, less than 1 nM or even less thanabout 0.5 nM. In some other embodiments, one or more subject compoundsexhibit dual binding specificity and are capable of inhibiting a PI3kinase (e.g., a class I PI3 kinase) as well as a protein kinase (e.g.,mTor) with an IC₅₀ value less than about 1 μM, less than about 100 nM,less than about 50 nM, less than about 10 nM, less than 1 nM or evenless than about 0.5 nM. One or more subject compounds are capable ofinhibiting tyrosine kinases including, for example, DNA-dependentprotein kinase (Pubmed protein accession number (PPAN) AAA79184), Abltyrosine kinase (CAA52387), Bcr-Abl, hemopoietic cell kinase (PPANCAI19695), Src (PPAN CAA24495), vascular endothelial growth factorreceptor 2 (PPAN ABB82619), vascular endothelial growth factorreceptor-2 (PPAN ABB82619), epidermal growth factor receptor (PPANAG43241), EPH receptor B4 (PPAN EAL23820), stem cell factor receptor(PPAN AAF22141), Tyrosine-protein kinase receptor TIE-2 (PPAN Q02858),fms-related tyrosine kinase 3 (PPAN NP_004110), platelet-derived growthfactor receptor alpha (PPAN NP_990080), RET (PPAN CAA73131), andfunctional mutants thereof. In some embodiments, the tyrosine kinase isAbl, Bcr-Abl, EGFR, or Flt-3, and any other kinases listed in the Tablesherein.

In some embodiments, non-limiting exemplary compounds exhibit one ormore functional characteristics provided herein. For example, one ormore subject compounds bind specifically to a PI3 kinase. In someembodiments, the IC₅₀ of a subject compound for p110α, p110β, p110γ, orp110δ is less than about 1 μM, less than about 100 nM, less than about50 nM, less than about 10 nM, less than about 1 nM, less than about 0.5nM, less than about 100 pM, or less than about 50 pM.

In some embodiments, one or more of the subject compounds canselectively inhibit one or more members of type I or class Iphosphatidylinositol 3-kinases (PI3-kinase) with an IC₅₀ value of about100 nM, 50 nM, 10 nM, 5 nM, 100 pM, 10 pM or 1 pM, or less as measuredin an in vitro kinase assay.

In some embodiments, one or more of the subject compounds canselectively inhibit one or two members of type I or class Iphosphatidylinositol 3-kinases (PI3-kinase) such as PI3-kinase α,PI3-kinase β, PI3-kinase γ, and PI3-kinase δ. In some aspects, some ofthe subject compounds selectively inhibit PI3-kinase δ as compared toall other type I PI3-kinases. In other aspects, some of the subjectcompounds selectively inhibit PI3-kinase δ and PI3-kinase γ as comparedto the rest of the type I PI3-kinases. In yet other aspects, some of thesubject compounds selectively inhibit PI3-kinase α and PI3-kinase β ascompared to the rest of the type I PI3-kinases. In still yet some otheraspects, some of the subject compounds selectively inhibit PI3-kinase δand PI3-kinase α as compared to the rest of the type I PI3-kinases. Instill yet some other aspects, some of the subject compounds selectivelyinhibit PI3-kinase δ and PI3-kinase β as compared to the rest of thetype I PI3-kinases, or selectively inhibit PI3-kinase δ and PI3-kinase αas compared to the rest of the type I PI3-kinases, or selectivelyinhibit PI3-kinase α and PI3-kinase γ as compared to the rest of thetype I PI3-kinases, or selectively inhibit PI3-kinase γ and PI3-kinase βas compared to the rest of the type I PI3-kinases.

In yet another aspect, an inhibitor that selectively inhibits one ormore members of type I PI3-kinases, or an inhibitor that selectivelyinhibits one or more type I PI3-kinase mediated signaling pathways,alternatively can be understood to refer to a compound that exhibits a50% inhibitory concentration (IC₅₀) with respect to a given type IPI3-kinase, that is at least about 10-fold, at least about 20-fold, atleast about 50-fold, at least about 100-fold, at least about 1000-fold,at least about 10,000-fold, or lower, than the inhibitor's IC₅₀ withrespect to the rest of the other type I PI3-kinases. In one embodiment,an inhibitor selectively inhibits PI3-kinase δ as compared to PI3-kinaseβ with at least about 10-fold lower IC₅₀ for PI3-kinase δ. In certainembodiments, the IC₅₀ for PI3-kinase δ is below about 100 nM, while theIC₅₀ for PI3-kinase β is above about 1000 nM. In certain embodiments,the IC₅₀ for PI3-kinase δ is below about 50 nM, while the IC₅₀ forPI3-kinase β is above about 5000 nM. In certain embodiments, the IC₅₀for PI3-kinase δ is below about 10 nM, while the IC₅₀ for PI3-kinase βis above about 1000 nM, above about 5,000 nM, or above about 10,000 nM.

Pharmaceutical Compositions

In some embodiments, provided herein are pharmaceutical compositionscomprising one or more compounds as provided herein, or apharmaceutically acceptable form thereof (e.g., pharmaceuticallyacceptable salts, hydrates, solvates, isomers, prodrugs, andisotopically labeled derivatives), and one or more pharmaceuticallyacceptable excipients carriers, including inert solid diluents andfillers, diluents, including sterile aqueous solution and variousorganic solvents, permeation enhancers, solubilizers and adjuvants. Insome embodiments, a pharmaceutical composition described herein includesa second active agent such as an additional therapeutic agent, (e.g., achemotherapeutic).

1. Formulations

Pharmaceutical compositions can be specially formulated foradministration in solid or liquid form, including those adapted for thefollowing: oral administration, for example, drenches (aqueous ornon-aqueous solutions or suspensions), tablets (e.g., those targeted forbuccal, sublingual, and systemic absorption), capsules, boluses,powders, granules, pastes for application to the tongue, andintraduodenal routes; parenteral administration, including intravenous,intraarterial, subcutaneous, intramuscular, intravascular,intraperitoneal or infusion as, for example, a sterile solution orsuspension, or sustained-release formulation; topical application, forexample, as a cream, ointment, or a controlled-release patch or sprayapplied to the skin; intravaginally or intrarectally, for example, as apessary, cream, stent or foam; sublingually; ocularly; pulmonarily;local delivery by catheter or stent; intrathecally, or nasally.

Examples of suitable aqueous and nonaqueous carriers which can beemployed in pharmaceutical compositions include water, ethanol, polyols(such as glycerol, propylene glycol, polyethylene glycol, and the like),and suitable mixtures thereof, vegetable oils, such as olive oil, andinjectable organic esters, such as ethyl oleate. Proper fluidity can bemaintained, for example, by the use of coating materials, such aslecithin, by the maintenance of the required particle size in the caseof dispersions, and by the use of surfactants.

These compositions can also contain adjuvants such as preservatives,wetting agents, emulsifying agents, dispersing agents, lubricants,and/or antioxidants. Prevention of the action of microorganisms upon thecompounds described herein can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It can also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form can be brought about by the inclusionof agents which delay absorption such as aluminum monostearate andgelatin.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound described herein and/or thechemotherapeutic with the carrier and, optionally, one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association a compound as provided herein withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Preparations for such pharmaceutical compositions are well-known in theart. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, WilliamG, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill,2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition,Churchill Livingston, N.Y., 1990; Katzung, ed., Basic and ClinicalPharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman,eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGrawHill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., LippincottWilliams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia,Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all ofwhich are incorporated by reference herein in their entirety. Exceptinsofar as any conventional excipient medium is incompatible with thecompounds provided herein, such as by producing any undesirablebiological effect or otherwise interacting in a deleterious manner withany other component(s) of the pharmaceutically acceptable composition,the excipient's use is contemplated to be within the scope of thisdisclosure.

In some embodiments, the concentration of one or more of the compoundsprovided in the disclosed pharmaceutical compositions is less than about100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%,about 30%, about 20%, about 19%, about 18%, about 17%, about 16%, about15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%,about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%,about 1%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%,about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about0.04%, about 0.03%, about 0.02%, about 0.01%, about 0.009%, about0.008%, about 0.007%, about 0.006%, about 0.005%, about 0.004%, about0.003%, about 0.002%, about 0.001%, about 0.0009%, about 0.0008%, about0.0007%, about 0.0006%, about 0.0005%, about 0.0004%, about 0.0003%,about 0.0002%, or about 0.0001% w/w, w/v or v/v.

In some embodiments, the concentration of one or more of the compoundsas provided herein is greater than about 90%, about 80%, about 70%,about 60%, about 50%, about 40%, about 30%, about 20%, about 19.75%,about 19.50%, about 19.25% about 19%, about 18.75%, about 18.50%, about18.25%, about 18%, about 17.75%, about 17.50%, about 17.25%, about 17%,about 16.75%, about 16.50%, about 16.25%, about 16%, about 15.75%, about15.50%, about 15.25%, about 15%, about 14.75%, about 14.50%, about14.25%, about 14%, about 13.75%, about 13.50%, about 13.25%, about 13%,about 12.75%, about 12.50%, about 12.25%, about 12%, about 11.75%, about11.50%, about 11.25%, about 11%, about 10.75%, about 10.50%, about10.25%, about 10%, about 9.75%, about 90.50%, about 9.25%, about 9%,about 8.75%, about 8.50%, about 8.25%, about 8%, about 7.75%, about7.50%, about 7.25%, about 7%, about 6.75%, about 6.50%, about 6.25%,about 6%, about 5.75%, about 5.50%, about 5.25%, about 5%, about 4.75%,about 4.50%, about 4.25%, about 4%, about 3.75%, about 3.50%, about3.25%, about 3%, about 2.75%, about 2.50%, about 2.25%, about 2%, about1.75%, about 1.50%, about 1.25%, about 1%, about 0.5%, about 0.4%, about0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%,about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about0.01%, about 0.009%, about 0.008%, about 0.007%, about 0.006%, about0.005%, about 0.004%, about 0.003%, about 0.002%, about 0.001%, about0.0009%, about 0.0008%, about 0.0007%, about 0.0006%, about 0.0005%,about 0.0004%, about 0.0003%, about 0.0002%, or about 0.0001% w/w, w/v,or v/v.

In some embodiments, the concentration of one or more of the compoundsas provided herein is in the range from approximately 0.0001% toapproximately 50%, approximately 0.001% to approximately 40%,approximately 0.01% to approximately 30%, approximately 0.02% toapproximately 29%, approximately 0.03% to approximately 28%,approximately 0.04% to approximately 27%, approximately 0.05% toapproximately 26%, approximately 0.06% to approximately 25%,approximately 0.07% to approximately 24%, approximately 0.08% toapproximately 23%, approximately 0.09% to approximately 22%,approximately 0.1% to approximately 21%, approximately 0.2% toapproximately 20%, approximately 0.3% to approximately 19%,approximately 0.4% to approximately 18%, approximately 0.5% toapproximately 17%, approximately 0.6% to approximately 16%,approximately 0.7% to approximately 15%, approximately 0.8% toapproximately 14%, approximately 0.9% to approximately 12%,approximately 1% to approximately 10% w/w, w/v or v/v. v/v.

In some embodiments, the concentration of one or more of the compoundsas provided herein is in the range from approximately 0.001% toapproximately 10%, approximately 0.01% to approximately 5%,approximately 0.02% to approximately 4.5%, approximately 0.03% toapproximately 4%, approximately 0.04% to approximately 3.5%,approximately 0.05% to approximately 3%, approximately 0.06% toapproximately 2.5%, approximately 0.07% to approximately 2%,approximately 0.08% to approximately 1.5%, approximately 0.09% toapproximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v orv/v.

In some embodiments, the amount of one or more of the compounds asprovided herein is equal to or less than about 10 g, about 9.5 g, about9.0 g, about 8.5 g, about 8.0 g, 7.5 g, about 7.0 g, about 6.5 g, about6.0 g, about 5.5 g, about 5.0 g, about 4.5 g, about 4.0 g, about 3.5 g,about 3.0 g, about 2.5 g, about 2.0 g, about 1.5 g, about 1.0 g, about0.95 g, about 0.9 g, about 0.85 g, about 0.8 g, about 0.75 g, about 0.7g, about 0.65 g, about 0.6 g, about 0.55 g, about 0.5 g, about 0.45 g,about 0.4 g, about 0.35 g, about 0.3 g, about 0.25 g, about 0.2 g, about0.15 g, about 0.1 g, about 0.09 g, about 0.08 g, about 0.07 g, about0.06 g, about 0.05 g, about 0.04 g, about 0.03 g, about 0.02 g, about0.01 g, about 0.009 g, about 0.008 g, about 0.007 g, about 0.006 g,about 0.005 g, about 0.004 g, about 0.003 g, about 0.002 g, about 0.001g, about 0.0009 g, about 0.0008 g, about 0.0007 g, about 0.0006 g, about0.0005 g, about 0.0004 g, about 0.0003 g, about 0.0002 g, or about0.0001 g.

In some embodiments, the amount of one or more of the compounds asprovided herein is more than about 0.0001 g, about 0.0002 g, about0.0003 g, about 0.0004 g, about 0.0005 g, about 0.0006 g, about 0.0007g, about 0.0008 g, about 0.0009 g, about 0.001 g, about 0.0015 g, about0.002 g, about 0.0025 g, about 0.003 g, about 0.0035 g, about 0.004 g,about 0.0045 g, about 0.005 g, about 0.0055 g, about 0.006 g, about0.0065 g, about 0.007 g, about 0.0075 g, about 0.008 g, about 0.0085 g,about 0.009 g, about 0.0095 g, about 0.01 g, about 0.015 g, about 0.02g, about 0.025 g, about 0.03 g, about 0.035 g, about 0.04 g, about 0.045g, about 0.05 g, about 0.055 g, about 0.06 g, about 0.065 g, about 0.07g, about 0.075 g, about 0.08 g, about 0.085 g, about 0.09 g, about 0.095g, about 0.1 g, about 0.15 g, about 0.2 g, about 0.25 g, about 0.3 g,about 0.35 g, about 0.4 g, about 0.45 g, about 0.5 g, about 0.55 g,about 0.6 g, about 0.65 g, about 0.7 g, about 0.75 g, about 0.8 g, about0.85 g, about 0.9 g, about 0.95 g, about 1 g, about 1.5 g, about 2 g,about 2.5, about 3 g, about 3.5, about 4 g, about 4.5 g, about 5 g,about 5.5 g, about 6 g, about 6.5 g, about 7 g, about 7.5 g, about 8 g,about 8.5 g, about 9 g, about 9.5 g, or about 10 g.

In some embodiments, the amount of one or more of the compounds asprovided herein is in the range of about 0.0001-about 10 g, about0.0005-about 9 g, about 0.001-about 8 g, about 0.005-about 7 g, about0.01-about 6 g, about 0.05-about 5 g, about 0.1-about 4 g, about0.5-about 4 g, or about 1-about 3 g.

1A. Formulations for Oral Administration

In some embodiments, provided herein are pharmaceutical compositions fororal administration containing a compound as provided herein, and apharmaceutical excipient suitable for oral administration. In someembodiments, provided herein are pharmaceutical compositions for oraladministration containing: (i) an effective amount of a disclosedcompound; optionally (ii) an effective amount of one or more secondagents; and (iii) one or more pharmaceutical excipients suitable fororal administration. In some embodiments, the pharmaceutical compositionfurther contains: (iv) an effective amount of a third agent.

In some embodiments, the pharmaceutical composition can be a liquidpharmaceutical composition suitable for oral consumption. Pharmaceuticalcompositions suitable for oral administration can be presented asdiscrete dosage forms, such as capsules, cachets, or tablets, or liquidsor aerosol sprays each containing a predetermined amount of an activeingredient as a powder or in granules, a solution, or a suspension in anaqueous or non-aqueous liquid, an oil-in-water emulsion, or awater-in-oil liquid emulsion. Such dosage forms can be prepared by anyof the methods of pharmacy, but all methods include the step of bringingthe active ingredient into association with the carrier, whichconstitutes one or more ingredients. In general, the pharmaceuticalcompositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product into the desiredpresentation. For example, a tablet can be prepared by compression ormolding, optionally with one or more accessory ingredients. Compressedtablets can be prepared by compressing in a suitable machine the activeingredient in a free-flowing form such as powder or granules, optionallymixed with an excipient such as, but not limited to, a binder, alubricant, an inert diluent, and/or a surface active or dispersingagent. Molded tablets can be made by molding in a suitable machine amixture of the powdered compound moistened with an inert liquid diluent.

The present disclosure further encompasses anhydrous pharmaceuticalcompositions and dosage forms comprising an active ingredient, sincewater can facilitate the degradation of some compounds. For example,water can be added (e.g., about 5%) in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. Anhydrous pharmaceutical compositions and dosage forms can beprepared using anhydrous or low moisture containing ingredients and lowmoisture or low humidity conditions. For example, pharmaceuticalcompositions and dosage forms which contain lactose can be madeanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected. An anhydrouspharmaceutical composition can be prepared and stored such that itsanhydrous nature is maintained. Accordingly, anhydrous pharmaceuticalcompositions can be packaged using materials known to prevent exposureto water such that they can be included in suitable formulary kits.Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastic or the like, unit dose containers,blister packs, and strip packs.

An active ingredient can be combined in an intimate admixture with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier can take a wide variety of formsdepending on the form of preparation desired for administration. Inpreparing the pharmaceutical compositions for an oral dosage form, anyof the usual pharmaceutical media can be employed as carriers, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents, and the like in the case of oral liquidpreparations (such as suspensions, solutions, and elixirs) or aerosols;or carriers such as starches, sugars, micro-crystalline cellulose,diluents, granulating agents, lubricants, binders, and disintegratingagents can be used in the case of oral solid preparations, in someembodiments without employing the use of lactose. For example, suitablecarriers include powders, capsules, and tablets, with the solid oralpreparations. In some embodiments, tablets can be coated by standardaqueous or nonaqueous techniques.

Binders suitable for use in pharmaceutical compositions and dosage formsinclude, but are not limited to, corn starch, potato starch, or otherstarches, gelatin, natural and synthetic gums such as acacia, sodiumalginate, alginic acid, other alginates, powdered tragacanth, guar gum,cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate,carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixturesthereof.

Examples of suitable fillers for use in the pharmaceutical compositionsand dosage forms provided herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

Disintegrants can be used in the pharmaceutical compositions as providedherein to provide tablets that disintegrate when exposed to an aqueousenvironment. Too much of a disintegrant can produce tablets which candisintegrate in the bottle. Too little can be insufficient fordisintegration to occur and can thus alter the rate and extent ofrelease of the active ingredient(s) from the dosage form. Thus, asufficient amount of disintegrant that is neither too little nor toomuch to detrimentally alter the release of the active ingredient(s) canbe used to form the dosage forms of the compounds provided herein. Theamount of disintegrant used can vary based upon the type of formulationand mode of administration, and can be readily discernible to those ofordinary skill in the art. About 0.5 to about 15 weight percent ofdisintegrant, or about 1 to about 5 weight percent of disintegrant, canbe used in the pharmaceutical composition. Disintegrants that can beused to form pharmaceutical compositions and dosage forms include, butare not limited to, agar-agar, alginic acid, calcium carbonate,microcrystalline cellulose, croscarmellose sodium, crospovidone,polacrilin potassium, sodium starch glycolate, potato or tapioca starch,other starches, pre-gelatinized starch, other starches, clays, otheralgins, other celluloses, gums or mixtures thereof.

Lubricants which can be used to form pharmaceutical compositions anddosage forms include, but are not limited to, calcium stearate,magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol,mannitol, polyethylene glycol, other glycols, stearic acid, sodiumlauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil,cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, ormixtures thereof. Additional lubricants include, for example, a syloidsilica gel, a coagulated aerosol of synthetic silica, or mixturesthereof. A lubricant can optionally be added, in an amount of less thanabout 1 weight percent of the pharmaceutical composition.

When aqueous suspensions and/or elixirs are desired for oraladministration, the active ingredient therein can be combined withvarious sweetening or flavoring agents, coloring matter or dyes and, forexample, emulsifying and/or suspending agents, together with suchdiluents as water, ethanol, propylene glycol, glycerin and variouscombinations thereof.

The tablets can be uncoated or coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate canbe employed. Formulations for oral use can also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example, peanut oil, liquidparaffin or olive oil.

Surfactant which can be used to form pharmaceutical compositions anddosage forms include, but are not limited to, hydrophilic surfactants,lipophilic surfactants, and mixtures thereof. That is, a mixture ofhydrophilic surfactants can be employed, a mixture of lipophilicsurfactants can be employed, or a mixture of at least one hydrophilicsurfactant and at least one lipophilic surfactant can be employed.

A suitable hydrophilic surfactant can generally have an HLB value of atleast about 10, while suitable lipophilic surfactants can generally havean HLB value of or less than about 10. An empirical parameter used tocharacterize the relative hydrophilicity and hydrophobicity of non-ionicamphiphilic compounds is the hydrophilic-lipophilic balance (“HLB”value). Surfactants with lower HLB values are more lipophilic orhydrophobic, and have greater solubility in oils, while surfactants withhigher HLB values are more hydrophilic, and have greater solubility inaqueous solutions. Hydrophilic surfactants are generally considered tobe those compounds having an HLB value greater than about 10, as well asanionic, cationic, or zwitterionic compounds for which the HLB scale isnot generally applicable. Similarly, lipophilic (i.e., hydrophobic)surfactants are compounds having an HLB value equal to or less thanabout 10. However, HLB value of a surfactant is merely a rough guidegenerally used to enable formulation of industrial, pharmaceutical andcosmetic emulsions.

Hydrophilic surfactants can be either ionic or non-ionic. Suitable ionicsurfactants include, but are not limited to, alkylammonium salts;fusidic acid salts; fatty acid derivatives of amino acids,oligopeptides, and polypeptides; glyceride derivatives of amino acids,oligopeptides, and polypeptides; lecithins and hydrogenated lecithins;lysolecithins and hydrogenated lysolecithins; phospholipids andderivatives thereof; lysophospholipids and derivatives thereof;carnitine fatty acid ester salts; salts of alkylsulfates; fatty acidsalts; sodium docusate; acylactylates; mono- and di-acetylated tartaricacid esters of mono- and di-glycerides; succinylated mono- anddi-glycerides; citric acid esters of mono- and di-glycerides; andmixtures thereof.

Within the aforementioned group, ionic surfactants include, by way ofexample: lecithins, lysolecithin, phospholipids, lysophospholipids andderivatives thereof; carnitine fatty acid ester salts; salts ofalkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono-and di-acetylated tartaric acid esters of mono- and di-glycerides;succinylated mono- and di-glycerides; citric acid esters of mono- anddi-glycerides; and mixtures thereof.

Ionic surfactants can be the ionized forms of lecithin, lysolecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol,phosphatidic acid, phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholylsarcosine, caproate, caprylate,caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate,linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate,lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, andsalts and mixtures thereof.

Hydrophilic non-ionic surfactants can include, but are not limited to,alkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; polyoxyalkylene alkyl ethers such as polyethyleneglycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethyleneglycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esterssuch as polyethylene glycol fatty acids monoesters and polyethyleneglycol fatty acids diesters; polyethylene glycol glycerol fatty acidesters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fattyacid esters such as polyethylene glycol sorbitan fatty acid esters;hydrophilic transesterification products of a polyol with at least onemember of glycerides, vegetable oils, hydrogenated vegetable oils, fattyacids, and sterols; polyoxyethylene sterols, derivatives, and analoguesthereof; polyoxyethylated vitamins and derivatives thereof;polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof;polyethylene glycol sorbitan fatty acid esters and hydrophilictransesterification products of a polyol with at least one member oftriglycerides, vegetable oils, and hydrogenated vegetable oils. Thepolyol can be glycerol, ethylene glycol, polyethylene glycol, sorbitol,propylene glycol, pentaerythritol, or a saccharide.

Other hydrophilic-non-ionic surfactants include, without limitation,PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate,PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate,PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryllaurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenatedcastor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitanlaurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearylether, tocopheryl PEG-100 succinate, PEG-24 cholesterol,polyglyceyl-10oleate, Tween 40, Tween 60, sucrose monostearate, sucrosemonolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG15-100 octyl phenol series, and poloxamers.

Suitable lipophilic surfactants include, by way of example only: fattyalcohols; glycerol fatty acid esters; acetylated glycerol fatty acidesters; lower alcohol fatty acids esters; propylene glycol fatty acidesters; sorbitan fatty acid esters; polyethylene glycol sorbitan fattyacid esters; sterols and sterol derivatives; polyoxyethylated sterolsand sterol derivatives; polyethylene glycol alkyl ethers; sugar esters;sugar ethers; lactic acid derivatives of mono- and di-glycerides;hydrophobic transesterification products of a polyol with at least onemember of glycerides, vegetable oils, hydrogenated vegetable oils, fattyacids and sterols; oil-soluble vitamins/vitamin derivatives; andmixtures thereof. Within this group, non-limiting examples of lipophilicsurfactants include glycerol fatty acid esters, propylene glycol fattyacid esters, and mixtures thereof, or are hydrophobictransesterification products of a polyol with at least one member ofvegetable oils, hydrogenated vegetable oils, and triglycerides.

In one embodiment, the pharmaceutical composition can include asolubilizer to ensure good solubilization and/or dissolution of acompound as provided herein and to minimize precipitation of thecompound. This can be especially important for pharmaceuticalcompositions for non-oral use, e.g., pharmaceutical compositions forinjection. A solubilizer can also be added to increase the solubility ofthe hydrophilic drug and/or other components, such as surfactants, or tomaintain the pharmaceutical composition as a stable or homogeneoussolution or dispersion.

Examples of suitable solubilizers include, but are not limited to, thefollowing: alcohols and polyols, such as ethanol, isopropanol, butanol,benzyl alcohol, ethylene glycol, propylene glycol, butanediols andisomers thereof, glycerol, pentaerythritol, sorbitol, mannitol,transcutol, dimethyl isosorbide, polyethylene glycol, polypropyleneglycol, polyvinylalcohol, hydroxypropyl methylcellulose and othercellulose derivatives, cyclodextrins and cyclodextrin derivatives;ethers of polyethylene glycols having an average molecular weight ofabout 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether(glycofurol) or methoxy PEG; amides and other nitrogen-containingcompounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam,N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esterssuch as ethyl propionate, tributylcitrate, acetyl triethylcitrate,acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate,ethyl butyrate, triacetin, propylene glycol monoacetate, propyleneglycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactoneand isomers thereof, β-butyrolactone and isomers thereof; and othersolubilizers known in the art, such as dimethyl acetamide, dimethylisosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycolmonoethyl ether, and water.

Mixtures of solubilizers can also be used. Examples include, but notlimited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate,dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone,polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol,transcutol, propylene glycol, and dimethyl isosorbide. In someembodiments, solubilizers include sorbitol, glycerol, triacetin, ethylalcohol, PEG-400, glycofurol and propylene glycol.

The amount of solubilizer that can be included is not particularlylimited. The amount of a given solubilizer can be limited to abioacceptable amount, which can be readily determined by one of skill inthe art. In some circumstances, it can be advantageous to includeamounts of solubilizers far in excess of bioacceptable amounts, forexample to maximize the concentration of the drug, with excesssolubilizer removed prior to providing the pharmaceutical composition toa subject using conventional techniques, such as distillation orevaporation. Thus, if present, the solubilizer can be in a weight ratioof about 10%, 25%, 50%, 100%, or up to about 200% by weight, based onthe combined weight of the drug, and other excipients. If desired, verysmall amounts of solubilizer can also be used, such as about 5%, 2%, 1%or even less. Typically, the solubilizer can be present in an amount ofabout 1% to about 100%, more typically about 5% to about 25% by weight.

The pharmaceutical composition can further include one or morepharmaceutically acceptable additives and excipients. Such additives andexcipients include, without limitation, detackifiers, anti-foamingagents, buffering agents, polymers, antioxidants, preservatives,chelating agents, viscomodulators, tonicifiers, flavorants, colorants,oils, odorants, opacifiers, suspending agents, binders, fillers,plasticizers, lubricants, and mixtures thereof.

Exemplary preservatives can include antioxidants, chelating agents,antimicrobial preservatives, antifungal preservatives, alcoholpreservatives, acidic preservatives, and other preservatives. Exemplaryantioxidants include, but are not limited to, alpha tocopherol, ascorbicacid, acorbyl palmitate, butylated hydroxyanisole, butylatedhydroxytoluene, monothioglycerol, potassium metabisulfite, propionicacid, propyl gallate, sodium ascorbate, sodium bisulfite, sodiummetabisulfite, and sodium sulfite. Exemplary chelating agents includeethylenediaminetetraacetic acid (EDTA), citric acid monohydrate,disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malicacid, phosphoric acid, sodium edetate, tartaric acid, and trisodiumedetate. Exemplary antimicrobial preservatives include, but are notlimited to, benzalkonium chloride, benzethonium chloride, benzylalcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine,chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol,glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethylalcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.Exemplary antifungal preservatives include, but are not limited to,butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoicacid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodiumbenzoate, sodium propionate, and sorbic acid. Exemplary alcoholpreservatives include, but are not limited to, ethanol, polyethyleneglycol, phenol, phenolic compounds, bisphenol, chlorobutanol,hydroxybenzoate, and phenylethyl alcohol. Exemplary acidic preservativesinclude, but are not limited to, vitamin A, vitamin C, vitamin E,beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbicacid, sorbic acid, and phytic acid. Other preservatives include, but arenot limited to, tocopherol, tocopherol acetate, deteroxime mesylate,cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened(BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ethersulfate (SLES), sodium bisulfite, sodium metabisulfite, potassiumsulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben,Germall 115, Germaben II, Neolone, Kathon, and Euxyl. In certainembodiments, the preservative is an anti-oxidant. In other embodiments,the preservative is a chelating agent.

Exemplary oils include, but are not limited to, almond, apricot kernel,avocado, babassu, bergamot, black current seed, borage, cade, camomile,canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, codliver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose,fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop,isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon,litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink,nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel,peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary,safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, sheabutter, silicone, soybean, sunflower, tea tree, thistle, tsubaki,vetiver, walnut, and wheat germ oils. Exemplary oils include, but arenot limited to, butyl stearate, caprylic triglyceride, caprictriglyceride, cyclomethicone, diethyl sebacate, dimethicone 360,isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol,silicone oil, and combinations thereof.

In addition, an acid or a base can be incorporated into thepharmaceutical composition to facilitate processing, to enhancestability, or for other reasons. Examples of pharmaceutically acceptablebases include amino acids, amino acid esters, ammonium hydroxide,potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate,aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesiumaluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite,magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine,ethylenediamine, triethanolamine, triethylamine, triisopropanolamine,trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like.Also suitable are bases that are salts of a pharmaceutically acceptableacid, such as acetic acid, acrylic acid, adipic acid, alginic acid,alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boricacid, butyric acid, carbonic acid, citric acid, fatty acids, formicacid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbicacid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonicacid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearicacid, succinic acid, tannic acid, tartaric acid, thioglycolic acid,toluenesulfonic acid, uric acid, and the like. Salts of polyproticacids, such as sodium phosphate, disodium hydrogen phosphate, and sodiumdihydrogen phosphate can also be used. When the base is a salt, thecation can be any convenient and pharmaceutically acceptable cation,such as ammonium, alkali metals, alkaline earth metals, and the like.Examples can include, but not limited to, sodium, potassium, lithium,magnesium, calcium and ammonium.

Suitable acids are pharmaceutically acceptable organic or inorganicacids. Examples of suitable inorganic acids include hydrochloric acid,hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boricacid, phosphoric acid, and the like. Examples of suitable organic acidsinclude acetic acid, acrylic acid, adipic acid, alginic acid,alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boricacid, butyric acid, carbonic acid, citric acid, fatty acids, formicacid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbicacid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid,para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid,thioglycolic acid, toluenesulfonic acid, uric acid and the like.

1B. Formulations for Parenteral Administration

In some embodiments, provided herein are pharmaceutical compositions forparenteral administration containing a compound as provided herein, anda pharmaceutical excipient suitable for parenteral administration. Insome embodiments, provided herein are pharmaceutical compositions forparenteral administration containing: (i) an effective amount of adisclosed compound; optionally (ii) an effective amount of one or moresecond agents; and (iii) one or more pharmaceutical excipients suitablefor parenteral administration. In some embodiments, the pharmaceuticalcomposition further contains: (iv) an effective amount of a third agent.

The forms in which the disclosed pharmaceutical compositions can beincorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles.

Aqueous solutions in saline are also conventionally used for injection.Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and thelike (and suitable mixtures thereof), cyclodextrin derivatives, andvegetable oils can also be employed.

Aqueous solutions in saline are also conventionally used for injection.Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and thelike (and suitable mixtures thereof), cyclodextrin derivatives, andvegetable oils can also be employed. The proper fluidity can bemaintained, for example, by the use of a coating, such as lecithin, forthe maintenance of the required particle size in the case of dispersionand by the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating a compound asprovided herein in the required amount in the appropriate solvent withvarious other ingredients as enumerated above, as appropriate, followedby filtered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the appropriateother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, certainmethods of preparation are vacuum-drying and freeze-drying techniqueswhich yield a powder of the active ingredient plus any additionalingredient from a previously sterile-filtered solution thereof.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use. Injectable compositions can contain from about 0.1to about 5% w/w of a compound as disclosed herein.

1C. Formulations for Topical Administration

In some embodiments, provided herein are pharmaceutical compositions fortopical (e.g., transdermal) administration containing a compound asprovided herein, and a pharmaceutical excipient suitable for topicaladministration. In some embodiments, provided herein are pharmaceuticalcompositions for topical administration containing: (i) an effectiveamount of a disclosed compound; optionally (ii) an effective amount ofone or more second agents; and (iii) one or more pharmaceuticalexcipients suitable for topical administration. In some embodiments, thepharmaceutical composition further contains: (iv) an effective amount ofa third agent.

Pharmaceutical compositions provided herein can be formulated intopreparations in solid, semi-solid, or liquid forms suitable for local ortopical administration, such as gels, water soluble jellies, creams,lotions, suspensions, foams, powders, slurries, ointments, solutions,oils, pastes, suppositories, sprays, emulsions, saline solutions,dimethylsulfoxide (DMSO)-based solutions. In general, carriers withhigher densities are capable of providing an area with a prolongedexposure to the active ingredients. In contrast, a solution formulationcan provide more immediate exposure of the active ingredient to thechosen area.

The pharmaceutical compositions also can comprise suitable solid or gelphase carriers or excipients, which are compounds that allow increasedpenetration of, or assist in the delivery of, therapeutic moleculesacross the stratum corneum permeability barrier of the skin. There aremany of these penetration-enhancing molecules known to those trained inthe art of topical formulation. Examples of such carriers and excipientsinclude, but are not limited to, humectants (e.g., urea), glycols (e.g.,propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleicacid), surfactants (e.g., isopropyl myristate and sodium laurylsulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes(e.g., menthol), amines, amides, alkanes, alkanols, water, calciumcarbonate, calcium phosphate, various sugars, starches, cellulosederivatives, gelatin, and polymers such as polyethylene glycols.

Another exemplary formulation for use in the disclosed methods employstransdermal delivery devices (“patches”). Such transdermal patches canbe used to provide continuous or discontinuous infusion of a compound asprovided herein in controlled amounts, either with or without anotheragent.

The construction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art. See, e.g., U.S. Pat.Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches can be constructedfor continuous, pulsatile, or on demand delivery of pharmaceuticalagents.

Suitable devices for use in delivering intradermal pharmaceuticallyacceptable compositions described herein include short needle devicessuch as those described in U.S. Pat. Nos. 4,886,499; 5,190,521;5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496; and 5,417,662.Intradermal compositions can be administered by devices which limit theeffective penetration length of a needle into the skin, such as thosedescribed in PCT publication WO 99/34850 and functional equivalentsthereof. Jet injection devices which deliver liquid vaccines to thedermis via a liquid jet injector and/or via a needle which pierces thestratum corneum and produces a jet which reaches the dermis aresuitable. Jet injection devices are described, for example, in U.S. Pat.Nos. 5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189;5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335;5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880;4,940,460; and PCT publications WO 97/37705 and WO 97/13537. Ballisticpowder/particle delivery devices which use compressed gas to acceleratevaccine in powder form through the outer layers of the skin to thedermis are suitable. Alternatively or additionally, conventionalsyringes can be used in the classical mantoux method of intradermaladministration.

Topically-administrable formulations can, for example, comprise fromabout 1% to about 10% (w/w) compound of formula (I), although theconcentration of the compound of formula (I) can be as high as thesolubility limit of the compound of formula (I) in the solvent. In someembodiments, topically-administrable formulations can, for example,comprise from about 1% to about 9% (w/w) compound of formula (I), suchas from about 1% to about 8% (w/w), further such as from about 1% toabout 7% (w/w), further such as from about 1% to about 6% (w/w), furthersuch as from about 1% to about 5% (w/w), further such as from about 1%to about 4% (w/w), further such as from about 1% to about 3% (w/w), andfurther such as from about 1% to about 2% (w/w) compound of formula (I).Formulations for topical administration can further comprise one or moreof the additional pharmaceutically acceptable excipients describedherein.

1D. Formulations for Inhalation Administration

In some embodiments, provided herein are pharmaceutical compositions forinhalation administration containing a compound as provided herein, anda pharmaceutical excipient suitable for topical administration. In someembodiments, provided herein are pharmaceutical compositions forinhalation administration containing: (i) an effective amount of adisclosed compound; optionally (ii) an effective amount of one or moresecond agents; and (iii) one or more pharmaceutical excipients suitablefor inhalation administration. In some embodiments, the pharmaceuticalcomposition further contains: (iv) an effective amount of a third agent.

Pharmaceutical compositions for inhalation or insufflation includesolutions and suspensions in pharmaceutically acceptable, aqueous ororganic solvents, or mixtures thereof, and powders. The liquid or solidpharmaceutical compositions can contain suitable pharmaceuticallyacceptable excipients as described herein. In some embodiments, thepharmaceutical compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Pharmaceuticalcompositions in pharmaceutically acceptable solvents can be nebulized byuse of inert gases. Nebulized solutions can be inhaled directly from thenebulizing device or the nebulizing device can be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder pharmaceutical compositions can beadministered, e.g., orally or nasally, from devices that deliver theformulation in an appropriate manner.

1E. Formulations for Ocular Administration

In some embodiments, the disclosure provides a pharmaceuticalcomposition for treating ophthalmic disorders. The pharmaceuticalcomposition can contain an effective amount of a compound as providedherein and a pharmaceutical excipient suitable for ocularadministration. Pharmaceutical compositions suitable for ocularadministration can be presented as discrete dosage forms, such as dropsor sprays each containing a predetermined amount of an active ingredienta solution, or a suspension in an aqueous or non-aqueous liquid, anoil-in-water emulsion, or a water-in-oil liquid emulsion. Otheradministration forms include intraocular injection, intravitrealinjection, topically, or through the use of a drug eluting device,microcapsule, implant, or microfluidic device. In some cases, thecompounds as provided herein are administered with a carrier orexcipient that increases the intraocular penetrance of the compound suchas an oil and water emulsion with colloid particles having an oily coresurrounded by an interfacial film. It is contemplated that all localroutes to the eye can be used including topical, subconjunctival,periocular, retrobulbar, subtenon, intracameral, intravitreal,intraocular, subretinal, juxtascleral and suprachoroidal administration.Systemic or parenteral administration can be feasible including, but notlimited to intravenous, subcutaneous, and oral delivery. An exemplarymethod of administration will be intravitreal or subtenon injection ofsolutions or suspensions, or intravitreal or subtenon placement ofbioerodible or non-bioerodible devices, or by topical ocularadministration of solutions or suspensions, or posterior juxtascleraladministration of a gel or cream formulation.

Eye drops can be prepared by dissolving the active ingredient in asterile aqueous solution such as physiological saline, bufferingsolution, etc., or by combining powder compositions to be dissolvedbefore use. Other vehicles can be chosen, as is known in the art,including, but not limited to: balance salt solution, saline solution,water soluble polyethers such as polyethyene glycol, polyvinyls, such aspolyvinyl alcohol and povidone, cellulose derivatives such asmethylcellulose and hydroxypropyl methylcellulose, petroleum derivativessuch as mineral oil and white petrolatum, animal fats such as lanolin,polymers of acrylic acid such as carboxypolymethylene gel, vegetablefats such as peanut oil and polysaccharides such as dextrans, andglycosaminoglycans such as sodium hyaluronate. In some embodiments,additives ordinarily used in the eye drops can be added. Such additivesinclude isotonizing agents (e.g., sodium chloride, etc.), buffer agent(e.g., boric acid, sodium monohydrogen phosphate, sodium dihydrogenphosphate, etc.), preservatives (e.g., benzalkonium chloride,benzethonium chloride, chlorobutanol, etc.), thickeners (e.g.,saccharide such as lactose, mannitol, maltose, etc.; e.g., hyaluronicacid or its salt such as sodium hyaluronate, potassium hyaluronate,etc.; e.g., mucopolysaccharide such as chondroitin sulfate, etc.; e.g.,sodium polyacrylate, carboxyvinyl polymer, crosslinked polyacrylate,polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose,hydroxy propyl cellulose or other agents known to those skilled in theart).

In some cases, the colloid particles include at least one cationic agentand at least one non-ionic surfactant such as a poloxamer, tyloxapol, apolysorbate, a polyoxyethylene castor oil derivative, a sorbitan ester,or a polyoxyl stearate. In some cases, the cationic agent is analkylamine, a tertiary alkyl amine, a quarternary ammonium compound, acationic lipid, an amino alcohol, a biguanidine salt, a cationiccompound or a mixture thereof. In some cases, the cationic agent is abiguanidine salt such as chlorhexidine, polyaminopropyl biguanidine,phenformin, alkylbiguanidine, or a mixture thereof. In some cases, thequaternary ammonium compound is a benzalkonium halide, lauralkoniumhalide, cetrimide, hexadecyltrimethylammonium halide,tetradecyltrimethylammonium halide, dodecyltrimethylammonium halide,cetrimonium halide, benzethonium halide, behenalkonium halide,cetalkonium halide, cetethyldimonium halide, cetylpyridinium halide,benzododecinium halide, chlorallyl methenamine halide, rnyristylalkoniumhalide, stearalkonium halide or a mixture of two or more thereof. Insome cases, cationic agent is a benzalkonium chloride, lauralkoniumchloride, benzododecinium bromide, benzethenium chloride,hexadecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide,dodecyltrimethylammonium bromide or a mixture of two or more thereof. Insome cases, the oil phase is mineral oil and light mineral oil, mediumchain triglycerides (MCT), coconut oil; hydrogenated oils comprisinghydrogenated cottonseed oil, hydrogenated palm oil, hydrogenate castoroil or hydrogenated soybean oil; polyoxyethylene hydrogenated castor oilderivatives comprising poluoxyl-40 hydrogenated castor oil, polyoxyl-60hydrogenated castor oil or polyoxyl-100 hydrogenated castor oil.

1F. Formulations for Controlled Release Administration

In some embodiments, provided herein are pharmaceutical compositions forcontrolled release administration containing a compound as providedherein, and a pharmaceutical excipient suitable for controlled releaseadministration. In some embodiments, provided herein are pharmaceuticalcompositions for controlled release administration containing: (i) aneffective amount of a disclosed compound; optionally (ii) an effectiveamount of one or more second agents; and (iii) one or morepharmaceutical excipients suitable for controlled releaseadministration. In some embodiments, the pharmaceutical compositionfurther contains: (iv) an effective amount of a third agent.

Active agents such as the compounds provided herein can be administeredby controlled release means or by delivery devices that are well knownto those of ordinary skill in the art. Examples include, but are notlimited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899;3,536,809; 3,598,123; and U.S. Pat. Nos. 4,008,719; 5,674,533;5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556;5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891;5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350;6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548;6,613,358; 6,699,500 each of which is incorporated herein by reference.Such dosage forms can be used to provide slow or controlled release ofone or more active agents using, for example, hydropropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmoticsystems, multilayer coatings, microparticles, liposomes, microspheres,or a combination thereof to provide the desired release profile invarying proportions. Suitable controlled release formulations known tothose of ordinary skill in the art, including those described herein,can be readily selected for use with the active agents provided herein.Thus, the pharmaceutical compositions provided encompass single unitdosage forms suitable for oral administration such as, but not limitedto, tablets, capsules, gelcaps, and caplets that are adapted forcontrolled release.

All controlled release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non controlledcounterparts. In some embodiments, the use of a controlled releasepreparation in medical treatment is characterized by a minimum of drugsubstance being employed to cure or control the disease, disorder, orcondition in a minimum amount of time. Advantages of controlled releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased subject compliance. In addition, controlledrelease formulations can be used to affect the time of onset of actionor other characteristics, such as blood levels of the drug, and can thusaffect the occurrence of side (e.g., adverse) effects.

In some embodiments, controlled release formulations are designed toinitially release an amount of a compound as provided herein thatpromptly produces the desired therapeutic effect, and gradually andcontinually release other amounts of the compound to maintain this levelof therapeutic or prophylactic effect over an extended period of time.In order to maintain this constant level of the compound in the body,the compound should be released from the dosage form at a rate that willreplace the amount of drug being metabolized and excreted from the body.Controlled release of an active agent can be stimulated by variousconditions including, but not limited to, pH, temperature, enzymes,water, or other physiological conditions or compounds.

In certain embodiments, the pharmaceutical composition can beadministered using intravenous infusion, an implantable osmotic pump, atransdermal patch, liposomes, or other modes of administration. In oneembodiment, a pump can be used (see, Sefton, CRC Crit. Ref Biomed. Eng.14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N.Engl. J. Med. 321:574 (1989)). In another embodiment, polymericmaterials can be used. In yet another embodiment, a controlled releasesystem can be placed in a subject at an appropriate site determined by apractitioner of skill, i.e., thus requiring only a fraction of thesystemic dose (see, e.g., Goodson, Medical Applications of ControlledRelease, 115-138 (vol. 2, 1984). Other controlled release systems arediscussed in the review by Langer, Science 249:1527-1533 (1990). The oneor more active agents can be dispersed in a solid inner matrix, e.g.,polymethylmethacrylate, polybutylmethacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinylalcohol andcross-linked partially hydrolyzed polyvinyl acetate, that is surroundedby an outer polymeric membrane, e.g., polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.The one or more active agents then diffuse through the outer polymericmembrane in a release rate controlling step. The percentage of activeagent in such parenteral compositions is highly dependent on thespecific nature thereof, as well as the needs of the subject.

2. Dosage

A compound described herein can be delivered in the form ofpharmaceutically acceptable compositions which comprise atherapeutically effective amount of one or more compounds describedherein and/or one or more additional therapeutic agents such as achemotherapeutic, formulated together with one or more pharmaceuticallyacceptable excipients. In some instances, the compound described hereinand the additional therapeutic agent are administered in separatepharmaceutical compositions and can (e.g., because of different physicaland/or chemical characteristics) be administered by different routes(e.g., one therapeutic is administered orally, while the other isadministered intravenously). In other instances, the compound describedherein and the additional therapeutic agent can be administeredseparately, but via the same route (e.g., both orally or bothintravenously). In still other instances, the compound described hereinand the additional therapeutic agent can be administered in the samepharmaceutical composition.

The selected dosage level will depend upon a variety of factorsincluding, for example, the activity of the particular compoundemployed, the route of administration, the time of administration, therate of excretion or metabolism of the particular compound beingemployed, the rate and extent of absorption, the duration of thetreatment, other drugs, compounds and/or materials used in combinationwith the particular compound employed, the age, sex, weight, condition,general health and prior medical history of the patient being treated,and like factors well known in the medical arts.

In general, a suitable daily dose of a compound described herein and/ora chemotherapeutic will be that amount of the compound which, in someembodiments, can be the lowest dose effective to produce a therapeuticeffect. Such an effective dose will generally depend upon the factorsdescribed above. Generally, doses of the compounds described herein fora patient, when used for the indicated effects, will range from about0.0001 mg to about 100 mg per day, or about 0.001 mg to about 100 mg perday, or about 0.01 mg to about 100 mg per day, or about 0.1 mg to about100 mg per day, or about 0.0001 mg to about 500 mg per day, or about0.001 mg to about 500 mg per day, or about 0.01 mg to 1000 mg, or about0.01 mg to about 500 mg per day, or about 0.1 mg to about 500 mg perday, or about 1 mg to 50 mg per day, or about 5 mg to 40 mg. Anexemplary dosage is about 10 to 30 mg per day. In some embodiments, fora 70 kg human, a suitable dose would be about 0.05 to about 7 g/day,such as about 0.05 to about 2.5 g/day. Actual dosage levels of theactive ingredients in the pharmaceutical compositions described hereincan be varied so as to obtain an amount of the active ingredient whichis effective to achieve the desired therapeutic response for aparticular patient, composition, and mode of administration, withoutbeing toxic to the patient. In some instances, dosage levels below thelower limit of the aforesaid range can be more than adequate, while inother cases still larger doses can be employed without causing anyharmful side effect, e.g., by dividing such larger doses into severalsmall doses for administration throughout the day.

In some embodiments, the compounds can be administered daily, everyother day, three times a week, twice a week, weekly, or bi-weekly. Thedosing schedule can include a “drug holiday,” i.e., the drug can beadministered for two weeks on, one week off, or three weeks on, one weekoff, or four weeks on, one week off, etc., or continuously, without adrug holiday. The compounds can be administered orally, intravenously,intraperitoneally, topically, transdermally, intramuscularly,subcutaneously, intranasally, sublingually, or by any other route.

In some embodiments, a compound as provided herein is administered inmultiple doses. Dosing can be about once, twice, three times, fourtimes, five times, six times, or more than six times per day. Dosing canbe about once a month, about once every two weeks, about once a week, orabout once every other day. In another embodiment, a compound asprovided herein and another agent are administered together about onceper day to about 6 times per day. In another embodiment, theadministration of a compound as provided herein and an agent continuesfor less than about 7 days. In yet another embodiment, theadministration continues for more than about 6, about 10, about 14,about 28 days, about two months, about six months, or about one year. Insome cases, continuous dosing is achieved and maintained as long asnecessary.

Administration of the pharmaceutical compositions as provided herein cancontinue as long as necessary. In some embodiments, an agent as providedherein is administered for more than about 1, about 2, about 3, about 4,about 5, about 6, about 7, about 14, or about 28 days. In someembodiments, an agent as provided herein is administered for less thanabout 28, about 14, about 7, about 6, about 5, about 4, about 3, about2, or about 1 day. In some embodiments, an agent as provided herein isadministered chronically on an ongoing basis, e.g., for the treatment ofchronic effects.

Since the compounds described herein can be administered in combinationwith other treatments (such as additional chemotherapeutics, radiationor surgery), the doses of each agent or therapy can be lower than thecorresponding dose for single-agent therapy. The dose for single-agenttherapy can range from, for example, about 0.0001 to about 200 mg, orabout 0.001 to about 100 mg, or about 0.01 to about 100 mg, or about 0.1to about 100 mg, or about 1 to about 50 mg per kilogram of body weightper day.

When a compound provided herein, is administered in a pharmaceuticalcomposition that comprises one or more agents, and the agent has ashorter half-life than the compound provided herein unit dose forms ofthe agent and the compound provided herein can be adjusted accordingly.

3. Kits

In some embodiments, provided herein are kits. The kits can include acompound or pharmaceutical composition as described herein, in suitablepackaging, and written material that can include instructions for use,discussion of clinical studies, listing of side effects, and the like.Such kits can also include information, such as scientific literaturereferences, package insert materials, clinical trial results, and/orsummaries of these and the like, which indicate or establish theactivities and/or advantages of the pharmaceutical composition, and/orwhich describe dosing, administration, side effects, drug interactions,or other information useful to the health care provider. Suchinformation can be based on the results of various studies, for example,studies using experimental animals involving in vivo models and studiesbased on human clinical trials.

In some embodiments, a memory aid is provided with the kit, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card, e.g., as follows “First Week, Monday,Tuesday, . . . etc. . . . . Second Week, Monday, Tuesday, . . . ” etc.Other variations of memory aids will be readily apparent. A “daily dose”can be a single tablet or capsule or several tablets or capsules to betaken on a given day.

The kit can further contain another agent. In some embodiments, thecompound as provided herein and the agent are provided as separatepharmaceutical compositions in separate containers within the kit. Insome embodiments, the compound as provided herein and the agent areprovided as a single pharmaceutical composition within a container inthe kit. Suitable packaging and additional articles for use (e.g.,measuring cup for liquid preparations, foil wrapping to minimizeexposure to air, and the like) are known in the art and can be includedin the kit. In other embodiments, kits can further comprise devices thatare used to administer the active agents. Examples of such devicesinclude, but are not limited to, syringes, drip bags, patches, andinhalers. Kits described herein can be provided, marketed and/orpromoted to health providers, including physicians, nurses, pharmacists,formulary officials, and the like. Kits can also, in some embodiments,be marketed directly to the consumer.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process, recesses are formed in theplastic foil. The recesses have the size and shape of the tablets orcapsules to be packed. Next, the tablets or capsules are placed in therecesses and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are sealed in the recesses between the plastic foil and thesheet. The strength of the sheet is such that the tablets or capsulescan be removed from the blister pack by manually applying pressure onthe recesses whereby an opening is formed in the sheet at the place ofthe recess. The tablet or capsule can then be removed via said opening.

Kits can further comprise pharmaceutically acceptable vehicles that canbe used to administer one or more active agents. For example, if anactive agent is provided in a solid form that must be reconstituted forparenteral administration, the kit can comprise a sealed container of asuitable vehicle in which the active agent can be dissolved to form aparticulate-free sterile solution that is suitable for parenteraladministration. Examples of pharmaceutically acceptable vehiclesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

The present disclosure further encompasses anhydrous pharmaceuticalcompositions and dosage forms comprising an active ingredient, sincewater can facilitate the degradation of some compounds. For example,water can be added (e.g., about 5%) in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. Anhydrous pharmaceutical compositions and dosage forms can beprepared using anhydrous or low moisture containing ingredients and lowmoisture or low humidity conditions. For example, pharmaceuticalcompositions and dosage forms which contain lactose can be madeanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected. An anhydrouspharmaceutical composition can be prepared and stored such that itsanhydrous nature is maintained. Accordingly, anhydrous pharmaceuticalcompositions can be packaged using materials known to prevent exposureto water such that they can be included in suitable formulary kits.Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastic or the like, unit dose containers,blister packs, and strip packs.

Therapeutic Methods

Phosphoinositide 3-kinases (PI3Ks) are members of a conserved family oflipid kinases that regulate numerous cell functions, includingproliferation, differentiation, cell survival and metabolism. Severalclasses of PI3Ks exist in mammalian cells, including Class IA subgroup(e.g., PI3K-α, β, δ), which are generally activated by receptor tyrosinekinases (RTKs); Class IB (e.g., PI3K-γ), which is activated by G-proteincoupled receptors (GPCRs), among others. PI3Ks exert their biologicalactivities via a “PI3K-mediated signaling pathway” that includes severalcomponents that directly and/or indirectly transduce a signal triggeredby a PI3K, including the generation of second messengerphophotidylinositol, 3, 4, 5-triphosphate (PIP3) at the plasma membrane,activation of heterotrimeric G protein signaling, and generation offurther second messengers such as cAMP, DAG, and IP3, all of which leadsto an extensive cascade of protein kinase activation (reviewed inVanhaesebroeck, B. et al. (2001) Annu Rev Biochem. 70:535-602). Forexample, PI3K-δ is activated by cellular receptors through interactionbetween the PI3K regulatory subunit (p85) SH2 domains, or through directinteraction with RAS. PIP3 produced by PI3K activates effector pathwaysdownstream through interaction with plextrin homology (PH) domaincontaining enzymes (e.g., PDK-1 and AKT [PKB]). (Fung-Leung W P. (2011)Cell Signal. 23(4):603-8). Unlike PI3K-δ, PI3K-γ is not associated witha regulatory subunit of the p85 family, but rather with a regulatorysubunit in the p101 family. PI3K-γ is associated with GPCRs, and isresponsible for the very rapid induction of PIP3. PI3K-γ can be alsoactivated by RAS.

In some embodiments, provided herein are methods of modulating a PI3Kkinase activity (e.g., selectively modulating) by contacting the kinasewith an effective amount of a compound, or a pharmaceutically acceptableform (e.g., pharmaceutically acceptable salts, hydrates, solvates,isomers, prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein. Modulation can beinhibition (e.g., reduction) or activation (e.g., enhancement) of kinaseactivity. In some embodiments, provided herein are methods of inhibitingkinase activity by contacting the kinase with an effective amount of acompound as provided herein in solution. In some embodiments, providedherein are methods of inhibiting the kinase activity by contacting acell, tissue, organ that express the kinase of interest with a compoundprovided herein. In some embodiments, provided herein are methods ofinhibiting kinase activity in a subject by administering into thesubject an effective amount of a compound as provided herein. In someembodiments, the kinase activity is inhibited (e.g., reduced) by morethan about 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% when contacted witha compound provided herein as compared to the kinase activity withoutsuch contact. In some embodiments, provided herein are methods ofinhibiting PI3 kinase activity in a subject (including mammals such ashumans) by contacting said subject with an amount of a compound asprovided herein sufficient to inhibit or reduce the activity of the PI3kinase in said subject.

In some embodiments, the kinase is a lipid kinase or a protein kinase.In some embodiments, the kinase is selected from a PI3 kinase includingdifferent isoforms such as PI3 kinase α, PI3 kinase β, PI3 kinase γ, PI3kinase δ; DNA-PK; mTor; Abl, VEGFR, Ephrin receptor B4 (EphB4); TEKreceptor tyrosine kinase (TIE2); FMS-related tyrosine kinase 3 (FLT-3);Platelet derived growth factor receptor (PDGFR); RET; ATM; ATR; hSmg-1;Hck; Src; Epidermal growth factor receptor (EGFR); KIT; Inulsin Receptor(IR); and IGFR.

As used herein, a “PI3K-mediated disorder” refers to a disease orcondition involving aberrant PI3K-mediated signaling pathway. In oneembodiment, provided herein is a method of treating a PI3K mediateddisorder in a subject, the method comprising administering atherapeutically effective amount of a compound or a pharmaceuticalcomposition as provided herein. In some embodiments, provided herein isa method of treating a PI3K-δ or PI3K-γ mediated disorder in a subject,the method comprising administering a therapeutically effective amountof a compound or a pharmaceutical composition as provided herein. Insome embodiments, provided herein is a method for inhibiting at leastone of PI3K-δ and PI3K-γ, the method comprising contacting a cellexpressing PI3K in vitro or in vivo with an effective amount of thecompound or composition provided herein. PI3Ks have been associated witha wide range of conditions, including immunity, cancer and thrombosis(reviewed in Vanhaesebroeck, B. et al. (2010) Current Topics inMicrobiology and Immunology, DOI 10.1007/82_2010_65). For example, ClassI PI3Ks, particularly PI3K-γ and PI3K-δ isoforms, are highly expressedin leukocytes and have been associated with adaptive and innateimmunity; thus, these PI3Ks are believed to be important mediators ininflammatory disorders and hematologic malignancies (reviewed in Harris,S J et al. (2009) Curr Opin Investig Drugs 10(11):1151-62); Rommel C. etal. (2007) Nat Rev Immunol 7(3):191-201; Durand C A et al. (2009) JImmunol. 183(9):5673-84; Dil N, Marshall A J. (2009) Mol Immunol.46(10):1970-8; Al-Alwan M M et al. (2007) J Immunol. 178(4):2328-35;Zhang T T, et al. (2008) J Allergy Clin Immunol. 2008;122(4):811-819.e2; Srinivasan L, et al. (2009) Cell 139(3):573-86).

Numerous publications support roles of PI3K-δ, PI3K-γ, and PI3K-β in thedifferentiation, maintenance, and activation of immune and malignantcells, as described in more detail below.

The importance of PI3K-δ in the development and function of B-cells issupported from inhibitor studies and genetic models. PI3K-δ is animportant mediator of B-cell receptor (BCR) signaling, and is upstreamof AKT, calcium flux, PLCγ, MAP kinase, P70S6k, and FOXO3a activation.PI3K-δ is also important in IL4R, S1P, and CXCR⁵ signaling, and has beenshown to modulate responses to toll-like receptors 4 and 9. Inhibitorsof PI3K-δ have shown the importance of PI3K-δ in B-cell development(Marginal zone and B1 cells), B-cell activation, chemotaxis, migrationand homing to lymphoid tissue, and in the control of immunoglobulinclass switching leading to the production of IgE. Clayton E et al.(2002) J Exp Med. 196(6):753-63; Bilancio A, et al. (2006) Blood107(2):642-50; Okkenhaug K. et al. (2002) Science 297(5583):1031-4;Al-Alwan M M et al. (2007) J Immunol. 178(4):2328-35; Zhang T T, et al.(2008) J Allergy Clin Immunol. 2008; 122(4):811-819.e2; Srinivasan L, etal. (2009) Cell 139(3):573-86)

In T-cells, PI3K-δ has been demonstrated to have a role in T-cellreceptor and cytokine signaling, and is upstream of AKT, PLCγ, andGSK3b. In PI3K-δ deletion or kinase-dead knock-in mice, or in inhibitorstudies, T-cell defects including proliferation, activation, anddifferentiation have been observed, leading to reduced T helper cell 2(TH2) response, memory T-cell specific defects (DTH reduction), defectsin antigen dependent cellular trafficking, and defects inchemotaxis/migration to chemokines (e.g., S1P, CCR7, CD62L). (Garcon F.et al. (2008) Blood 111(3):1464-71; Okkenhaug K et al. (2006). JImmunol. 177(8):5122-8; Soond D R, et al. (2010) Blood 115(11):2203-13;Reif K, (2004). J Immunol. 2004; 173(4):2236-40; Ji H. et al. (2007)Blood 110(8):2940-7; Webb L M, et al. (2005) J Immunol. 175(5):2783-7;Liu D, et al. (2010) J Immunol. 184(6):3098-105; Haylock-Jacobs S, etal. (2011) J Autoimmun. 2011; 36(3-4):278-87; Jarmin S J, et al. (2008)J Clin Invest. 118(3):1154-64).

In neutrophils, PI3K-δ along with PI3K-γ, and PI3K-β, contribute to theresponses to immune complexes, FCγRII signaling, including migration andneutrophil respiratory burst. Human neutrophils undergo rapid inductionof PIP3 in response to formyl peptide receptor (FMLP) or complementcomponent C5a (C5a) in a PI3K-γ dependent manner, followed by a longerPIP3 production period that is PI3K-δ dependent, and is essential forrespiratory burst. The response to immune complexes is contributed byPI3K-δ, PI3K-γ, and PI3K-β, and is an important mediator of tissuedamage in models of autoimmune disease (Randis T M et al. (2008) Eur JImmunol. 38(5):1215-24; Pinho V, (2007) J Immunol. 179(11):7891-8; SadhuC. et al. (2003) J mmunol. 170(5):2647-54; Condliffe A M et al. (2005)Blood 106(4):1432-40). It has been reported that in certain autoimmunediseases, perfrential activation of PI3Kβ may be involved. (Kulkarni etal., Immunology (2011) 4(168) ra23: 1-11). It was also reported thatPI3Kβ-deficient mice were highly protected in an FcγR-dependent model ofautoantibody-induced skin blistering and partially protected in anFcγR-dependent model of inflammatory arthritis, whereas combineddeficiency of PI3Kβ and PI3Kδ resulted in near complete protection ininflammatory arthritis. (Id.).

In macrophages collected from patients with chronic obstructivepulmonary disease (COPD), glucocorticoid responsiveness can be restoredby treatment of the cells with inhibitors of PI3K-δ. Macrophages alsorely on PI3K-δ and PI3K-γ for responses to immune complexes through thearthus reaction (FCgR and C5a signaling) (Randis T M, et al. (2008) EurJ Immunol. 38(5):1215-24; Marwick J A et al. (2009) Am J Respir CritCare Med. 179(7):542-8; Konrad S, et al. (2008) J Biol Chem.283(48):33296-303).

In mast cells, stem cell factor-(SCF) and IL3-dependent proliferation,differentiation and function are PI3K-δ dependent, as is chemotaxis. Theallergen/IgE crosslinking of FCgR1 resulting in cytokine release anddegranulation of the mast cells is severely inhibited by treatment withPI3K-δ inhibitors, suggesting a role for PI3K-δ in allergic disease (AliK et al. (2004) Nature 431(7011):1007-11; Lee K S, et al. (2006) FASEBJ. 20(3):455-65; Kim M S, et al. (2008) Trends Immunol. 29(10):493-501).

Natural killer (NK) cells are dependent on both PI3K-δ and PI3K-γ forefficient migration towards chemokines including CXCL10, CCL3, S1P andCXCL12, or in response to LPS in the peritoneum (Guo H, et al. (2008) JExp Med. 205(10):2419-35; Tassi I, et al. (2007) Immunity 27(2):214-27;Saudemont A, (2009) Proc Natl Acad Sci USA. 106(14):5795-800; Kim N, etal. (2007) Blood 110(9):3202-8).

The roles of PI3K-δ, PI3K-γ, and PI3K-β in the differentiation,maintenance, and activation of immune cells support a role for theseenzymes in inflammatory disorders ranging from autoimmune diseases(e.g., rheumatoid arthritis, multiple sclerosis) to allergicinflammatory disorders, such as asthma, and inflammatory respiratorydisease such as COPD. Extensive evidence is available in experimentalanimal models, or can be evaluated using art-recognized animal models.In an embodiment, described herein is a method of treating inflammatorydisorders ranging from autoimmune diseases (e.g., rheumatoid arthritis,multiple sclerosis) to allergic inflammatory disorders, such as asthmaand COPD using a compound described herein.

For example, inhibitors of PI3K-δ and/or -γ have been shown to haveanti-inflammatory activity in several autoimmune animal models forrheumatoid arthritis (Williams, O. et al. (2010) Chem Biol,17(2):123-34; WO 2009/088986; WO2009/088880; WO 2011/008302). PI3K-δ isexpressed in the RA synovial tissue (especially in the synovial liningwhich contains fibroblast-like synoviocytes (FLS), and selective PI3K-δinhibitors have been shown to be effective in inhibiting synoviocytegrowth and survival (Bartok et al. (2010) Arthritis Rheum 62 Suppl10:362). Several PI3K-δ and -γ inhibitors have been shown to amelioratearthritic symptoms (e.g., swelling of joints, reduction of serum-inducedcollagen levels, reduction of joint pathology and/or inflammation), inart-recognized models for RA, such as collagen-induced arthritis andadjuvant induced arthritis (WO 2009/088986; WO2009/088880; WO2011/008302).

The role of PI3K-δ has also been shown in models of T-cell dependentresponse, including the DTH model. In the murine experimental autoimmuneencephalomyelitis (EAE) model of multiple sclerosis, the PI3K-γ/δ-doublemutant mice are resistant. PI3K-δ inhibitors have also been shown toblock EAE disease induction and development of TH-17 cells both in vitroand in vivo (Haylock-Jacobs, S. et al. (2011) J. Autoimmunity36(3-4):278-87).

Systemic lupus erythematosus (SLE) is a complex disease that atdifferent stages requires memory T-cells, B-cell polyclonal expansionand differentiation into plasma cells, and the innate immune response toendogenous damage associated molecular pattern molecules (DAMPS), andthe inflammatory responses to immune complexes through the complementsystem as well as the F_(C) receptors. The role of PI3K-δ and PI3K-γtogether in these pathways and cell types suggest that blockade with aninhibitor would be effective in these diseases. A role for PI3K in lupusis also predicted by two genetic models of lupus. The deletion ofphosphatase and tensin homolog (PTEN) leads to a lupus-like phenotype,as does a transgenic activation of Class1A PI3Ks, which includes PI3K-δ.The deletion of PI3K-γ in the transgenically activated class 1A lupusmodel is protective, and treatment with a PI3K-γ selective inhibitor inthe murine MLR/lpr model of lupus improves symptoms (Barber, D F et al.(2006) J. Immunol. 176(1): 589-93).

In allergic disease, PI3K-δ has been shown by genetic models and byinhibitor treatment to be essential for mast-cell activation in apassive cutaneous anaphalaxis assay (Ali K et al. (2008) J Immunol.180(4):2538-44; Ali K, (2004) Nature 431(7011):1007-11). In a pulmonarymeasure of response to immune complexes (Arthus reaction) a PI3K-δknockout is resistant, showing a defect in macrophage activation and C5aproduction. Knockout studies and studies with inhibitors for both PI3K-δand PI3K-γ support a role for both of these enzymes in the ovalbumininduced allergic airway inflammation and hyper-responsiveness model (LeeK S et al. (2006) FASEB J. 20(3):455-65). Reductions of infiltration ofeosinophils, neutrophils, and lymphocytes as well as TH2 cytokines (IL4,IL5, and IL13) were seen with both PI3K-δ specific and dual PI3K-δ andPI3K-γ inhibitors in the Ova induced asthma model (Lee K S et al. (2006)J Allergy Clin Immunol 118(2):403-9).

PI3K-δ and PI3K-γ inhibition can be used in treating COPD. In the smokedmouse model of COPD, the PI3K-δ knockout does not develop smoke inducedglucocorticoid resistance, while wild-type and PI3K-γ knockout mice do.An inhaled formulation of dual PI3K-δ and PI3K-γ inhibitor blockedinflammation in a LPS or smoke COPD models as measured by neutrophiliaand glucocorticoid resistance (Doukas J, et al. (2009) J Pharmacol ExpTher. 328(3):758-65).

Class I PI3Ks, particularly PI3K-δ and PI3K-γ isoforms, are alsoassociated with cancers (reviewed, e.g., in Vogt, P K et al. (2010) CurrTop Microbiol Immunol. 347:79-104; Fresno Vara, J A et al. (2004) CancerTreat Rev. 30(2):193-204; Zhao, L and Vogt, P K. (2008) Oncogene27(41):5486-96). Inhibitors of PI3K, e.g., PI3K-δ and/or -γ, have beenshown to have anti-cancer activity (e.g., Courtney, K D et al. (2010) JClin Oncol. 28(6):1075-1083); Markman, B et al. (2010) Ann Oncol.21(4):683-91; Kong, D and Yamori, T (2009) Curr Med Chem.16(22):2839-54; Jimeno, A et al. (2009) J Clin Oncol. 27:156s (suppl;abstr 3542); Flinn, I W et al. (2009) J Clin Oncol. 27:156s (suppl;abstr 3543); Shapiro, G et al. (2009) J Clin Oncol. 27:146s (suppl;abstr 3500); Wagner, A J et al. (2009) J Clin Oncol. 27:146s (suppl;abstr 3501); Vogt, P K et al. (2006) Virology 344(1):131-8; Ward, S etal. (2003) Chem Biol. 10(3):207-13; WO 2011/041399; US 2010/0029693; US2010/0305096; US 2010/0305084). In an embodiment, described herein is amethod of treating cancer.

Types of cancer that can be treated with an inhibitor of PI3K(particularly, PI3K-δ and/or -γ) include, e.g., leukemia, chroniclymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia(e.g., Salmena, L et al. (2008) Cell 133:403-414; Chapuis, N et al.(2010) Clin Cancer Res. 16(22):5424-35; Khwaja, A (2010) Curr TopMicrobiol Immunol. 347:169-88); lymphoma, e.g., non-Hodgkin's lymphoma(e.g., Salmena, L et al. (2008) Cell 133:403-414); lung cancer, e.g.,non-small cell lung cancer, small cell lung cancer (e.g., Herrera, V Aet al. (2011) Anticancer Res. 31(3):849-54); melanoma (e.g., Haluska, Fet al. (2007) Semin Oncol. 34(6):546-54); prostate cancer (e.g., Sarker,D et al. (2009) Clin Cancer Res. 15(15):4799-805); glioblastoma (e.g.,Chen, J S et al. (2008) Mol Cancer Ther. 7:841-850); endometrial cancer(e.g., Bansal, N et al. (2009) Cancer Control. 16(1):8-13); pancreaticcancer (e.g., Furukawa, T (2008) J Gastroenterol. 43(12):905-11); renalcell carcinoma (e.g., Porta, C and Figlin, R A (2009) J Urol.182(6):2569-77); colorectal cancer (e.g., Saif, M W and Chu, E (2010)Cancer J. 16(3):196-201); breast cancer (e.g., Torbett, N E et al.(2008) Biochem J. 415:97-100); thyroid cancer (e.g., Brzezianska, E andPastuszak-Lewandoska, D (2011) Front Biosci. 16:422-39); and ovariancancer (e.g., Mazzoletti, M and Broggini, M (2010) Curr Med Chem.17(36):4433-47).

Numerous publications support a role of PI3K-δ and PI3K-γ in treatinghematological cancers. PI3K-δ and PI3K-γ□ are highly expressed in theheme compartment, and some solid tumors, including prostate, breast andglioblastomas (Chen J. S. et al. (2008) Mol Cancer Ther. 7(4):841-50;Ikeda H. et al. (2010) Blood 116(9):1460-8).

In hematological cancers including acute myeloid leukemia (AML),multiple myeloma (MM), and chronic lymphocytic leukemia (CLL),overexpression and constitutive activation of PI3K-δ supports the modelthat PI3K-δ inhibition would be therapeutic Billottet C, et al. (2006)Oncogene 25(50):6648-59; Billottet C, et al. (2009) Cancer Res.69(3):1027-36; Meadows, S A, 52^(nd) Annual ASH Meeting and Exposition;2010 Dec. 4-7; Orlando, Fla.; Ikeda H, et al. (2010) Blood116(9):1460-8; Herman S E et al. (2010) Blood 116(12):2078-88; Herman SE et al. (2011). Blood 117(16):4323-7. In an embodiment, describedherein is a method of treating hematological cancers including, but notlimited to acute myeloid leukemia (AML), multiple myeloma (MM), andchronic lymphocytic leukemia (CLL).

A PI3K-δ inhibitor (CAL-101) has been evaluated in a phase 1 trial inpatients with haematological malignancies, and showed activity in CLL inpatients with poor prognostic characteristics. In CLL, inhibition ofPI3K-δ not only affects tumor cells directly, but it also affects theability of the tumor cells to interact with their microenvironment. Thismicroenvironment includes contact with and factors from stromal cells,T-cells, nurse like cells, as well as other tumor cells. CAL-101suppresses the expression of stromal and T-cell derived factorsincluding CCL3, CCL4, and CXCL13, as well as the CLL tumor cells'ability to respond to these factors. CAL-101 treatment in CLL patientsinduces rapid lymph node reduction and redistribution of lymphocytesinto the circulation, and affects tonic survival signals through theBCR, leading to reduced cell viability, and an increase in apoptosis.Single agent CAL-101 treatment was also active in mantle cell lymphomaand refractory non Hodgkin's lymphoma (Furman, R R, et al. 52^(nd)Annual ASH Meeting and Exposition; 2010 Dec. 4-7; Orlando, Fla.;Hoellenriegel, J, et al. 52^(nd) Annual ASH Meeting and Exposition; 2010Dec. 4-7; Orlando, Fla.; Webb, H K, et al. 52^(nd) Annual ASH Meetingand Exposition; 2010 Dec. 4-7; Orlando, Fla.; Meadows, et al. 52^(nd)Annual ASH Meeting and Exposition; 2010 Dec. 4-7; Orlando, Fla.; Kahl,B, et al. 52^(nd) Annual ASH Meeting and Exposition; 2010 Dec. 4-7;Orlando, Fla.; Lannutti B J, et al. (2011) Blood 117(2):591-4).

PI3K-δ inhibitors have shown activity against PI3K-δ positive gliomas invitro (Kashishian A, et al. Poster presented at: The AmericanAssociation of Cancer Research 102^(nd) Annual Meeting; 2011 Apr. 2-6;Orlando, Fla.). PI3K-δ is the PI3K isoform that is most commonlyactivated in tumors where the PTEN tumor suppressor is mutated (Ward S,et al. (2003) Chem Biol. 10(3):207-13). In this subset of tumors,treatment with the PI3K-δ inhibitor either alone or in combination witha cytotoxic agent can be effective.

Another mechanism for PI3K-δ inhibitors to have an affect in solidtumors involves the tumor cells' interaction with theirmicro-environment. PI3K-δ, PI3K-γ, and PI3K-β are expressed in theimmune cells that infiltrate tumors, including tumor infiltratinglymphocytes, macrophages, and neutrophils. PI3K-δ inhibitors can modifythe function of these tumor-associated immune cells and how they respondto signals from the stroma, the tumor, and each other, and in this wayaffect tumor cells and metastasis (Hoellenriegel, J, et al. 52^(nd)Annual ASH Meeting and Exposition; 2010 Dec. 4-7; Orlando, Fla.).

PI3K-δ is also expressed in endothelial cells. It has been shown thattumors in mice treated with PI3K-δ selective inhibitors are killed morereadily by radiation therapy. In this same study, capillary networkformation is impaired by the PI3K inhibitor, and it is postulated thatthis defect contributes to the greater killing with radiation. PI3K-δinhibitors can affect the way in which tumors interact with theirmicroenviroment, including stromal cells, immune cells, and endothelialcells and be therapeutic either on its own or in conjunction withanother therapy (Meadows, S A, et al. Paper presented at: 52^(nd) AnnualASH Meeting and Exposition; 2010 Dec. 4-7; Orlando, Fla.; Geng L, et al.(2004) Cancer Res. 64(14):4893-9).

In other embodiments, inhibition of PI3K (such as PI3K-δ and/or -γ) canbe used to treat a neuropsychiatric disorder, e.g., an autoimmune braindisorder. Infectious and immune factors have been implicated in thepathogenesis of several neuropsychiatric disorders, including, but notlimited to, Sydenham's chorea (SC) (Garvey, M. A. et al. (2005) J. ChildNeurol. 20:424-429), Tourette's syndrome (TS), obsessive compulsivedisorder (OCD) (Asbahr, F. R. et al. (1998) Am. J. Psychiatry155:1122-1124), attention deficit/hyperactivity disorder (AD/HD)(Hirschtritt, M. E. et al. (2008) Child Neuropsychol. 1:1-16; Peterson,B. S. et al. (2000) Arch. Gen. Psychiatry 57:364-372), anorexia nervosa(Sokol, M. S. (2000) J. Child Adolesc. Psychopharmacol. 10:133-145;Sokol, M. S. et al. (2002) Am. J. Psychiatry 159:1430-1432), depression(Leslie, D. L. et al. (2008) J. Am. Acad. Child Adolesc. Psychiatry47:1166-1172), and autism spectrum disorders (ASD) (Hollander, E. et al.(1999) Am. J. Psychiatry 156:317-320; Margutti, P. et al. (2006) Curr.Neurovasc. Res. 3:149-157). A subset of childhood obsessive compulsivedisorders and tic disorders has been grouped as Pediatric AutoimmuneNeuropsychiatric Disorders Associated with Streptococci (PANDAS). PANDASdisorders provide an example of disorders where the onset andexacerbation of neuropsychiatric symptoms is preceded by a streptococcalinfection (Kurlan, R., Kaplan, E. L. (2004) Pediatrics 113:883-886;Garvey, M. A. et al. (1998) J. Clin. Neurol. 13:413-423). Many of thePANDAS disorders share a common mechanism of action resulting fromantibody responses against streptococcal associated epitopes, such asGlcNAc, which produces neurological effects (Kirvan. C. A. et al. (2006)J. Neuroimmunol. 179:173-179). Autoantibodies recognizing centralnervous system (CNS) epitopes are also found in sera of most PANDASsubjects (Yaddanapudi, K. et al. (2010) Mol. Psychiatry 15:712-726).Thus, several neuropsychiatric disorders have been associated withimmune and autoimmune components, making them suitable for therapiesthat include PI3K-δ and/or -γ inhibition.

In certain embodiments, a method of treating (e.g., reducing orameliorating one or more symptoms of) a neuropsychiatric disorder,(e.g., an autoimmune brain disorder), using a PI3K-δ and/or -γ inhibitoris described, alone or in combination therapy. For example, one or morePI3K-δ and/or -γ inhibitors described herein can be used alone or incombination with any suitable therapeutic agent and/or modalities, e.g.,dietary supplement, for treatment of neuropsychiatric disorders.Exemplary neuropsychiatric disorders that can be treated with the PI3K-δand/or -γ inhibitors described herein include, but are not limited to,PANDAS disorders, Sydenham's chorea, Tourette's syndrome, obsessivecompulsive disorder, attention deficit/hyperactivity disorder, anorexianervosa, depression, and autism spectrum disorders. PervasiveDevelopmental Disorder (PDD) is an exemplary class of autism spectrumdisorders that includes Autistic Disorder, Asperger's Disorder,Childhood Disintegrative Disorder (CDD), Rett's Disorder and PDD-NotOtherwise Specified (PDD-NOS). Animal models for evaluating the activityof the PI3K-δ and/or -γ inhibitor are known in the art. For example, amouse model of PANDAS disorders is described in, e.g., Yaddanapudi, K.et al. (2010) supra; and Hoffman, K. I. et al. (2004) J. Neurosci.24:1780-1791.

In some embodiments, provided herein are methods of using the compounds,or a pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided hereinto treat disease conditions, including, but not limited to, diseasesassociated with malfunctioning of one or more types of PI3 kinase. Adetailed description of conditions and disorders mediated by p110δkinase activity is set forth in Sadu et al., WO 01/81346, which isincorporated herein by reference in its entirety for all purposes.

In some embodiments, the disclosure relates to a method of treating ahyperproliferative disorder in a subject that comprises administering tosaid subject a therapeutically effective amount of a compound, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein.In some embodiments, said method relates to the treatment of cancer suchas acute myeloid leukemia, thymus, brain, lung, squamous cell, skin,eye, retinoblastoma, intraocular melanoma, oral cavity andoropharyngeal, bladder, gastric, stomach, pancreatic, bladder, breast,cervical, head, neck, renal, kidney, liver, ovarian, prostate,colorectal, esophageal, testicular, gynecological, thyroid, CNS, PNS,AIDS-related (e.g., Lymphoma and Kaposi's Sarcoma) or viral-inducedcancer. In some embodiments, said method relates to the treatment of anon-cancerous hyperproliferative disorder such as benign hyperplasia ofthe skin (e. g., psoriasis), restenosis, or prostate (e. g., benignprostatic hypertrophy (BPH)).

Patients that can be treated with compounds, or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or pharmaceutical compositions as provided herein, according tothe methods as provided herein include, for example, but not limited to,patients that have been diagnosed as having psoriasis; restenosis;atherosclerosis; BPH; breast cancer such as a ductal carcinoma in ducttissue in a mammary gland, medullary carcinomas, colloid carcinomas,tubular carcinomas, and inflammatory breast cancer; ovarian cancer,including epithelial ovarian tumors such as adenocarcinoma in the ovaryand an adenocarcinoma that has migrated from the ovary into theabdominal cavity; uterine cancer; cervical cancer such as adenocarcinomain the cervix epithelial including squamous cell carcinoma andadenocarcinomas; prostate cancer, such as a prostate cancer selectedfrom the following: an adenocarcinoma or an adenocarinoma that hasmigrated to the bone; pancreatic cancer such as epitheliod carcinoma inthe pancreatic duct tissue and an adenocarcinoma in a pancreatic duct;bladder cancer such as a transitional cell carcinoma in urinary bladder,urothelial carcinomas (transitional cell carcinomas), tumors in theurothelial cells that line the bladder, squamous cell carcinomas,adenocarcinomas, and small cell cancers; leukemia such as acute myeloidleukemia (AML), acute lymphocytic leukemia, chronic lymphocyticleukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia,myeloproliferative disorders, NK cell leukemia (e.g., blasticplasmacytoid dendritic cell neoplasm), acute myelogenous leukemia (AML),chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocyticleukemia (CLL), multiple myeloma (MM), and myelodysplastic syndrome(MDS); bone cancer; lung cancer such as non-small cell lung cancer(NSCLC), which is divided into squamous cell carcinomas,adenocarcinomas, and large cell undifferentiated carcinomas, and smallcell lung cancer; skin cancer such as basal cell carcinoma, melanoma,squamous cell carcinoma and actinic keratosis, which is a skin conditionthat sometimes develops into squamous cell carcinoma; eyeretinoblastoma; cutaneous or intraocular (eye) melanoma; primary livercancer (cancer that begins in the liver); kidney cancer; thyroid cancersuch as papillary, follicular, medullary and anaplastic; lymphoma suchas diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma, NK celllymphoma (e.g., blastic plasmacytoid dendritic cell neoplasm), and smallnon-cleaved cell lymphoma; Kaposi's Sarcoma; viral-induced cancersincluding hepatitis B virus (HBV), hepatitis C virus (HCV), andhepatocellular carcinoma; human lymphotropic virus-type 1 (HTLV-1) andadult T-cell leukemia/lymphoma; and human papilloma virus (HPV) andcervical cancer; central nervous system cancers (CNS) such as primarybrain tumor, which includes gliomas (astrocytoma, anaplasticastrocytoma, or glioblastoma multiforme), Oligodendroglioma, Ependymoma,Meningioma, Lymphoma, Schwannoma, and Medulloblastoma; peripheralnervous system (PNS) cancers such as acoustic neuromas and malignantperipheral nerve sheath tumor (MPNST) including neurofibromas andschwannomas, malignant fibrous cytoma, malignant fibrous histiocytoma,malignant meningioma, malignant mesothelioma, and malignant mixedMüllerian tumor; oral cavity and oropharyngeal cancer such as,hypopharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, andoropharyngeal cancer; stomach cancer such as lymphomas, gastric stromaltumors, and carcinoid tumors; testicular cancer such as germ cell tumors(GCTs), which include seminomas and nonseminomas, and gonadal stromaltumors, which include Leydig cell tumors and Sertoli cell tumors; thymuscancer such as to thymomas, thymic carcinomas, Hodgkin disease,non-Hodgkin lymphomas carcinoids or carcinoid tumors; rectal cancer; andcolon cancer.

In one embodiment, provided herein is a method of treating aninflammation disorder, including autoimmune diseases in a subject. Themethod comprises administering to said subject a therapeuticallyeffective amount of a compound, or a pharmaceutically acceptable form(e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein. Examples of autoimmunediseases includes but is not limited to acute disseminatedencephalomyelitis (ADEM), Addison's disease, antiphospholipid antibodysyndrome (APS), aplastic anemia, autoimmune hepatitis, autoimmune skindisease, coeliac disease, Crohn's disease, Diabetes mellitus (type 1),Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS),Hashimoto's disease, lupus erythematosus, multiple sclerosis, myastheniagravis, opsoclonus myoclonus syndrome (OMS), optic neuritis, Ord'sthyroiditis, oemphigus, polyarthritis, primary biliary cirrhosis,psoriasis, rheumatoid arthritis, Reiter's syndrome, Takayasu'sarteritis, temporal arteritis (also known as “giant cell arteritis”),warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopeciauniversalis (e.g., inflammatory alopecia), Chagas disease, chronicfatigue syndrome, dysautonomia, endometriosis, hidradenitis suppurativa,interstitial cystitis, neuromyotonia, sarcoidosis, scleroderma,ulcerative colitis, vitiligo, and vulvodynia. Other disorders includebone-resorption disorders and thrombosis.

Inflammation takes on many forms and includes, but is not limited to,acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse,disseminated, exudative, fibrinous, fibrosing, focal, granulomatous,hyperplastic, hypertrophic, interstitial, metastatic, necrotic,obliterative, parenchymatous, plastic, productive, proliferous,pseudomembranous, purulent, sclerosing, seroplastic, serous, simple,specific, subacute, suppurative, toxic, traumatic, and/or ulcerativeinflammation.

Exemplary inflammatory conditions include, but are not limited to,inflammation associated with acne, anemia (e.g., aplastic anemia,haemolytic autoimmune anaemia), asthma, arteritis (e.g., polyarteritis,temporal arteritis, periarteritis nodosa, Takayasu's arteritis),arthritis (e.g., crystalline arthritis, osteoarthritis, psoriaticarthritis, gout flare, gouty arthritis, reactive arthritis, rheumatoidarthritis and Reiter's arthritis), ankylosing spondylitis, amylosis,amyotrophic lateral sclerosis, autoimmune diseases, allergies orallergic reactions, atherosclerosis, bronchitis, bursitis, chronicprostatitis, conjunctivitis, Chagas disease, chronic obstructivepulmonary disease, cermatomyositis, diverticulitis, diabetes (e.g., typeI diabetes mellitus, type 2 diabetes mellitus), a skin condition (e.g.,psoriasis, eczema, burns, dermatitis, pruritus (itch)), endometriosis,Guillain-Barre syndrome, infection, ischaemic heart disease, Kawasakidisease, glomerulonephritis, gingivitis, hypersensitivity, headaches(e.g., migraine headaches, tension headaches), ileus (e.g.,postoperative ileus and ileus during sepsis), idiopathicthrombocytopenic purpura, interstitial cystitis (painful bladdersyndrome), gastrointestinal disorder (e.g., selected from peptic ulcers,regional enteritis, diverticulitis, gastrointestinal bleeding,eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis,eosinophilic gastritis, eosinophilic gastroenteritis, eosinophiliccolitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, orits synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn'sdisease, ulcerative colitis, collagenous colitis, lymphocytic colitis,ischaemic colitis, diversion colitis, Behcet's syndrome, indeterminatecolitis) and inflammatory bowel syndrome (IBS)), lupus, multiplesclerosis, morphea, myeasthenia gravis, myocardial ischemia, nephroticsyndrome, pemphigus vulgaris, pernicious aneaemia, peptic ulcers,polymyositis, primary biliary cirrhosis, neuroinflammation associatedwith brain disorders (e.g., Parkinson's disease, Huntington's disease,and Alzheimer's disease), prostatitis, chronic inflammation associatedwith cranial radiation injury, pelvic inflammatory disease, polymyalgiarheumatic, reperfusion injury, regional enteritis, rheumatic fever,systemic lupus erythematosus, scleroderma, scierodoma, sarcoidosis,spondyloarthopathies, Sjogren's syndrome, thyroiditis, transplantationrejection, tendonitis, trauma or injury (e.g., frostbite, chemicalirritants, toxins, scarring, burns, physical injury), vasculitis,vitiligo and Wegener's granulomatosis. In certain embodiments, theinflammatory disorder is selected from arthritis (e.g., rheumatoidarthritis), inflammatory bowel disease, inflammatory bowel syndrome,asthma, psoriasis, endometriosis, interstitial cystitis andprostatistis. In certain embodiments, the inflammatory condition is anacute inflammatory condition (e.g., for example, inflammation resultingfrom infection). In certain embodiments, the inflammatory condition is achronic inflammatory condition (e.g., conditions resulting from asthma,arthritis and inflammatory bowel disease). The compounds can also beuseful in treating inflammation associated with trauma andnon-inflammatory myalgia.

Immune disorders, such as auto-immune disorders, include, but are notlimited to, arthritis (including rheumatoid arthritis,spondyloarthopathies, gouty arthritis, degenerative joint diseases suchas osteoarthritis, systemic lupus erythematosus, Sjogren's syndrome,ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease,haemolytic autoimmune anaemias, multiple sclerosis, amyotrophic lateralsclerosis, amylosis, acute painful shoulder, psoriatic, and juvenilearthritis), asthma, atherosclerosis, osteoporosis, bronchitis,tendonitis, bursitis, skin condition (e.g., psoriasis, eczema, burns,dermatitis, pruritus (itch)), enuresis, eosinophilic disease,gastrointestinal disorder (e.g., selected from peptic ulcers, regionalenteritis, diverticulitis, gastrointestinal bleeding, eosinophilicgastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilicgastritis, eosinophilic gastroenteritis, eosinophilic colitis),gastritis, diarrhea, gastroesophageal reflux disease (GORD, or itssynonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease,ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemiccolitis, diversion colitis, Behcet's syndrome, indeterminate colitis)and inflammatory bowel syndrome (IBS)), relapsing polychondritis (e.g.,atrophic polychondritis and systemic polychondromalacia), and disordersameliorated by a gastroprokinetic agent (e.g., ileus, postoperativeileus and ileus during sepsis; gastroesophageal reflux disease (GORD, orits synonym GERD); eosinophilic esophagitis, gastroparesis such asdiabetic gastroparesis; food intolerances and food allergies and otherfunctional bowel disorders, such as non-ulcerative dyspepsia (NUD) andnon-cardiac chest pain (NCCP, including costo-chondritis)). In certainembodiments, a method of treating inflammatory or autoimmune diseases isprovided comprising administering to a subject (e.g., a mammal) atherapeutically effective amount of a compound, or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or pharmaceutical compositions as provided herein, thatselectively inhibit PI3K-δ and/or PI3K-γ as compared to all other type IPI3 kinases.

Such selective inhibition of PI3K-δ and/or PI3K-γ can be advantageousfor treating any of the diseases or conditions described herein. Forexample, selective inhibition of PI3K-δ can inhibit inflammatoryresponses associated with inflammatory diseases, autoimmune disease, ordiseases related to an undesirable immune response including, but notlimited to asthma, emphysema, allergy, dermatitis, rheumatoid arthritis,psoriasis, lupus erythematosus, anaphylaxsis, or graft versus hostdisease. Selective inhibition of PI3K-δ can further provide for areduction in the inflammatory or undesirable immune response without aconcomittant reduction in the ability to reduce a bacterial, viral,and/or fungal infection. Selective inhibition of both PI3K-δ and PI3K-γcan be advantageous for inhibiting the inflammatory response in thesubject to a greater degree than that would be provided for byinhibitors that selectively inhibit PI3K-δ or PI3K-γ alone. In oneaspect, one or more of the subject methods are effective in reducingantigen specific antibody production in vivo by about 2-fold, 3-fold,4-fold, 5-fold, 7.5-fold, 10-fold, 25-fold, 50-fold, 100-fold, 250-fold,500-fold, 750-fold, or about 1000-fold or more. In another aspect, oneor more of the subject methods are effective in reducing antigenspecific IgG3 and/or IgGM production in vivo by about 2-fold, 3-fold,4-fold, 5-fold, 7.5-fold, 10-fold, 25-fold, 50-fold, 100-fold, 250-fold,500-fold, 750-fold, or about 1000-fold or more.

In one aspect, one of more of the subject methods are effective inameliorating symptoms associated with rheumatoid arthritis including,but not limited to a reduction in the swelling of joints, a reduction inserum anti-collagen levels, and/or a reduction in joint pathology suchas bone resorption, cartilage damage, pannus, and/or inflammation. Inanother aspect, the subject methods are effective in reducing ankleinflammation by at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 50%,60%, or about 75% to 90%. In another aspect, the subject methods areeffective in reducing knee inflammation by at least about 2%, 5%, 10%,15%, 20%, 25%, 30%, 50%, 60%, or about 75% to 90% or more. In stillanother aspect, the subject methods are effective in reducing serumanti-type II collagen levels by at least about 10%, 12%, 15%, 20%, 24%,25%, 30%, 35%, 50%, 60%, 75%, 80%, 86%, 87%, or about 90% or more. Inanother aspect, the subject methods are effective in reducing anklehistopathology scores by about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%,60%, 75%, 80%, 90% or more. In still another aspect, the subject methodsare effective in reducing knee histopathology scores by about 5%, 10%,15%, 20%, 25%, 30%, 40%, 50%, 60%, 75%, 80%, 90% or more.

In some embodiments, provided herein are methods for treating disordersor conditions in which the δ isoform of PI3K is implicated to a greaterextent than other PI3K isoforms such as PI3K-α and/or -β. Selectiveinhibition of PI3K-δ and/or PI3K-γ can provide advantages over usingless selective compounds which inhibit PI3K-α and/or -β, such as animproved side effects profile or lessened reduction in the ability toreduce a bacterial, viral, and/or fungal infection.

In other embodiments, provided herein are methods of using a compound,or a pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,to treat respiratory diseases including, but not limited to diseasesaffecting the lobes of lung, pleural cavity, bronchial tubes, trachea,upper respiratory tract, or the nerves and muscle for breathing. Forexample, methods are provided to treat obstructive pulmonary disease.Chronic obstructive pulmonary disease (COPD) is an umbrella term for agroup of respiratory tract diseases that are characterized by airflowobstruction or limitation. Conditions included in this umbrella terminclude, but are not limited to: chronic bronchitis, emphysema, andbronchiectasis.

In another embodiment, the compounds, or a pharmaceutically acceptableform (e.g., pharmaceutically acceptable salts, hydrates, solvates,isomers, prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein are used for thetreatment of asthma. Also, the compounds or pharmaceutical compositionsdescribed herein can be used for the treatment of endotoxemia andsepsis. In one embodiment, the compounds or pharmaceutical compositionsdescribed herein are used to for the treatment of rheumatoid arthritis(RA). In yet another embodiment, the compounds or pharmaceuticalcompositions described herein is used for the treatment of contact oratopic dermatitis. Contact dermatitis includes irritant dermatitis,phototoxic dermatitis, allergic dermatitis, photoallergic dermatitis,contact urticaria, systemic contact-type dermatitis and the like.Irritant dermatitis can occur when too much of a substance is used onthe skin of when the skin is sensitive to certain substance. Atopicdermatitis, sometimes called eczema, is a kind of dermatitis, an atopicskin disease.

In some embodiments, the disclosure provides a method of treatingdiseases related to vasculogenesis or angiogenesis in a subject thatcomprises administering to said subject a therapeutically effectiveamount of a compound, or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein. In some embodiments,said method is for treating a disease selected from tumor angiogenesis,chronic inflammatory disease such as rheumatoid arthritis and chronicinflammatory demyelinating polyneuropathy, atherosclerosis, inflammatorybowel disease, skin diseases such as psoriasis, eczema, and scleroderma,diabetes, diabetic retinopathy, retinopathy of prematurity, age-relatedmacular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma andovarian, breast, lung, pancreatic, prostate, colon and epidermoidcancer.

In addition, the compounds described herein can be used for thetreatment of arteriosclerosis, including atherosclerosis.Arteriosclerosis is a general term describing any hardening of medium orlarge arteries. Atherosclerosis is a hardening of an artery specificallydue to an atheromatous plaque.

In some embodiments, provided herein is a method of treating acardiovascular disease in a subject that comprises administering to saidsubject a therapeutically effective amount of a compound as providedherein, or a pharmaceutically acceptable form (e.g., pharmaceuticallyacceptable salts, hydrates, solvates, isomers, prodrugs, andisotopically labeled derivatives) thereof. Examples of cardiovascularconditions include, but are not limited to, atherosclerosis, restenosis,vascular occlusion and carotid obstructive disease.

In some embodiments, the disclosure relates to a method of treatingdiabetes in a subject that comprises administering to said subject atherapeutically effective amount of a compound as provided herein, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein.

In addition, the compounds, or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein, can be used to treatacne. In certain embodiments, the inflammatory condition and/or immunedisorder is a skin condition. In some embodiments, the skin condition ispruritus (itch), psoriasis, eczema, burns or dermatitis. In certainembodiments, the skin condition is psoriasis. In certain embodiments,the skin condition is pruritis.

In certain embodiments, the inflammatory disorder and/or the immunedisorder is a gastrointestinal disorder. In some embodiments, thegastrointestinal disorder is selected from gastrointestinal disorder(e.g., selected from peptic ulcers, regional enteritis, diverticulitis,gastrointestinal bleeding, eosinophilic gastrointestinal disorders(e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilicgastroenteritis, eosinophilic colitis), gastritis, diarrhea,gastroesophageal reflux disease (GORD, or its synonym GERD),inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerativecolitis, collagenous colitis, lymphocytic colitis, ischaemic colitis,diversion colitis, Behcet's syndrome, indeterminate colitis) andinflammatory bowel syndrome (IBS)). In certain embodiments, thegastrointestinal disorder is inflammatory bowel disease (IBD).

Further, the compounds, or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein, can be used for thetreatment of glomerulonephritis. Glomerulonephritis is a primary orsecondary autoimmune renal disease characterized by inflammation of theglomeruli. It can be asymptomatic, or present with hematuria and/orproteinuria. There are many recognized types, divided in acute, subacuteor chronic glomerulonephritis. Causes are infectious (bacterial, viralor parasitic pathogens), autoimmune or paraneoplastic.

In some embodiments, provided herein are compounds, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,for the treatment of multiorgan failure. Also provided herein arecompounds, or a pharmaceutically acceptable form (e.g., pharmaceuticallyacceptable salts, hydrates, solvates, isomers, prodrugs, andisotopically labeled derivatives) thereof, or pharmaceuticalcompositions as provided herein, for the treatment of liver diseases(including diabetes), gall bladder disease (including gallstones),pancreatitis or kidney disease (including proliferativeglomerulonephritis and diabetes-induced renal disease) or pain in asubject.

In some embodiments, provided herein are compounds, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,for the prevention of blastocyte implantation in a subject.

In some embodiments, provided herein are compounds, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,for the treatment of disorders involving platelet aggregation orplatelet adhesion, including, but not limited to Idiopathicthrombocytopenic purpura, Bernard-Soulier syndrome, Glanzmann'sthrombasthenia, Scott's syndrome, von Willebrand disease,Hermansky-Pudlak Syndrome, and Gray platelet syndrome.

In some embodiments, compounds, or a pharmaceutically acceptable form(e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein, are provided fortreating a disease which is skeletal muscle atrophy, skeletal or musclehypertrophy. In some embodiments, provided herein are compounds, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,for the treatment of disorders that include, but are not limited to,cancers as discussed herein, transplantation-related disorders (e.g.,lowering rejection rates, graft-versus-host disease, etc.), muscularsclerosis (MS), allergic disorders (e.g., arthritis, allergicencephalomyelitis) and other immunosuppressive-related disorders,metabolic disorders (e.g., diabetes), reducing intimal thickeningfollowing vascular injury, and misfolded protein disorders (e.g.,Alzheimer's Disease, Gaucher's Disease, Parkinson's Disease,Huntington's Disease, cystic fibrosis, macular degeneration, retinitispigmentosa, and prion disorders) (as mTOR inhibition can alleviate theeffects of misfolded protein aggregates). The disorders also includehamartoma syndromes, such as tuberous sclerosis and Cowden Disease (alsotermed Cowden syndrome and multiple hamartoma syndrome).

Additionally, the compounds, or a pharmaceutically acceptable form(e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein, can be used for thetreatment of bursitis, lupus, acute disseminated encephalomyelitis(ADEM), Addison's disease, antiphospholipid antibody syndrome (APS),amyloidosis (including systemic and localized amyloidosis; and primaryand secondary amyloidosis), aplastic anemia, autoimmune hepatitis,coeliac disease, crohn's disease, diabetes mellitus (type 1),eosinophilic gastroenterides, goodpasture's syndrome, graves' disease,guillain-barré syndrome (GBS), hashimoto's disease, inflammatory boweldisease, lupus erythematosus (including cutaneous lupus erythematosusand systemic lupus erythematosus), myasthenia gravis, opsoclonusmyoclonus syndrome (OMS), optic neuritis, ord's thyroiditis,ostheoarthritis, uveoretinitis, pemphigus, polyarthritis, primarybiliary cirrhosis, reiter's syndrome, takayasu's arteritis, temporalarteritis, warm autoimmune hemolytic anemia, wegener's granulomatosis,alopecia universalis, chagas' disease, chronic fatigue syndrome,dysautonomia, endometriosis, hidradenitis suppurativa, interstitialcystitis, neuromyotonia, sarcoidosis, scleroderma, ulcerative colitis,vitiligo, vulvodynia, appendicitis, arteritis, arthritis, blepharitis,bronchiolitis, bronchitis, cervicitis, cholangitis, cholecystitis,chorioamnionitis, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,gastroenteritis, gingivitis, hepatitis, hidradenitis, ileitis, iritis,laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis,nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, uveitis (e.g., ocular uveitis), vaginitis,vasculitis, or vulvitis.

In another aspect, provided herein are methods of disrupting thefunction of a leukocyte or disrupting a function of an osteoclast. Themethod includes contacting the leukocyte or the osteoclast with afunction disrupting amount of a compound as provided herein.

In another aspect, methods are provided for treating ophthalmic diseaseby administering one or more of the subject compounds or pharmaceuticalcompositions to the eye of a subject.

In certain embodiments, provided herein are methods of treating,preventing and/or managing a disease or a disorder using a compound, ora pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,wherein the disease or disorder is: Crohn's disease; cutaneous lupus;multiple sclerosis; rheumatoid arthritis; and systemic lupuserythematosus.

In other embodiments, provided herein are methods of treating,preventing and/or managing a disease or a disorder using a compound, ora pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,wherein the disease or disorder is: ankylosing spondylitis; chronicobstructive pulmonary disease; myasthenia gravis; ocular uveitis,psoriasis; and psoriatic arthritis.

In other embodiments, provided herein are methods of treating,preventing and/or managing a disease or a disorder using a compound, ora pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,wherein the disease or disorder is: adult-onset Still's disease;inflammatory alopecia; amyloidosis; antiphospholipid syndrome;autoimmune hepatitis; autoimmune skin disease, Behcet's disease; chronicinflammatory demyelinating polyneuropathy; eosinophilic gastroenteritis;inflammatory myopathies, pemphigus, polymyalgia rheumatica; relapsingpolychondritis; Sjorgen's syndrome; temporal arthritis; ulcerativecolitis; vasculis; vitiligo, and Wegner's granulomatosis.

In other embodiments, provided herein are methods of treating,preventing and/or managing a disease or a disorder using a compound, ora pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,wherein the disease or disorder is: gout flare; sacoidosis; and systemicsclerosis.

In certain embodiments, provided herein are methods of treating,preventing and/or managing a disease or a disorder using a compound, ora pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,wherein the disease or disorder is: asthma; arthritis (e.g., rheumatoidarthritis and psoriatic arthritis); psoriasis; scleroderma; myositis(e.g., dermatomyositis); lupus (e.g., cutaneous lupus erythematosus(“CLE”) or systemic lupus erythematosus (“SLE”)); or Sjögren's syndrome.

Efficacy of a compound provided herein in treating, preventing and/ormanaging the disease or disorder can be tested using various animalmodels known in the art. For example: efficacy in treating, preventingand/or managing asthma can be assessed using ova induced asthma modeldescribed, for example, in Lee et al. (2006) J Allergy Clin Immunol118(2):403-9; efficacy in treating, preventing and/or managing arthritis(e.g., rheumatoid or psoriatic arthritis) can be assessed usingautoimmune animal models described, for example, in Williams et al.(2010) Chem Biol, 17(2):123-34, WO 2009/088986, WO2009/088880, and WO2011/008302; efficacy in treating, preventing and/or managing psoriasiscan be assessed using transgenic or knockout mouse model with targetedmutations in epidermis, vasculature or immune cells, mouse modelresulting from spontaneous mutations, and immunodeficient mouse modelwith xenotransplantation of human skin or immune cells, all of which aredescribed, for example, in Boehncke et al. (2007) Clinics inDermatology, 25: 596-605; efficacy in treating, preventing and/ormanaging fibrosis or fibrotic condition can be assessed using theunilateral ureteral obstruction model of renal fibrosis (see Chevalieret al., Kidney International (2009) 75:1145-1152), the bleomycin inducedmodel of pulmonary fibrosis (see Moore and Hogaboam, Am. J. Physiol.Lung. Cell. Mol. Physiol. (2008) 294:L152-L160), a variety ofliver/biliary fibrosis models (see Chuang et al., Clin Liver Dis (2008)12:333-347 and Omenetti, A. et al. (2007) Laboratory Investigation87:499-514 (biliary duct-ligated model)), or a number of myelofibrosismouse models (see Varicchio, L. et al. (2009) Expert Rev. Hematol.2(3):315-334); efficacy in treating, preventing and/or managingscleroderma can be assessed using mouse model induced by repeated localinjections of bleomycin (“BLM”) described, for example, in Yamamoto etal. (1999) J Invest Dermatol 112: 456-462; efficacy in treating,preventing and/or managing dermatomyositis can be assessed usingmyositis mouse model induced by immunization with rabbit myosindescribed, for example, in Phyanagi et al. (2009) Arthritis &Rheumatism, 60(10): 3118-3127; efficacy in treating, preventing and/ormanaging lupus (e.g., CLE or SLE) can be assessed using various animalmodels described, for example, in Ghoreishi et al. (2009) Lupus, 19:1029-1035, Ohl et al. (2011) Journal of Biomedicine and Biotechnology,Article ID 432595 (14 pages), Xia et al. (2011) Rheumatology,50:2187-2196, Pau et al. (2012) PLoS ONE, 7(5):e36761 (15 pages),Mustafa et al. (2011) Toxicology, 290:156-168, Ichikawa et al. (2012)Arthritis and Rheumatism, 62(2): 493-503, Ouyang et al. (2012) J MolMed, DOI 10.1007/s00109-012-0866-3 (10 pages), Rankin et al. (2012)Journal of Immunology, 188:1656-1667; and efficacy in treating,preventing and/or managing Sjögren's syndrome can be assessed usingvarious mouse models described, for example, in Chiorini et al. (2009)Journal of Autoimmunity, 33: 190-196.

In one embodiment, provided herein is a method of treating, preventingand/or managing asthma. As used herein, “asthma” encompasses airwayconstriction regardless of the cause. Common triggers of asthma include,but are not limited to, exposure to an environmental stimulants (e.g.,allergens), cold air, warm air, perfume, moist air, exercise orexertion, and emotional stress. Also provided herein is a method oftreating, preventing and/or managing one or more symptoms associatedwith asthma. Examples of the symptoms include, but are not limited to,severe coughing, airway constriction and mucus production.

In one embodiment, provided herein is a method of treating, preventingand/or managing arthritis. As used herein, “arthritis” encompasses alltypes and manifestations of arthritis. Examples include, but are notlimited to, crystalline arthritis, osteoarthritis, psoriatic arthritis,gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter'sarthritis. In one embodiment, the disease or disorder is rheumatoidarthritis. In another embodiment, the disease or disorder is psoriaticarthritis. Also provided herein is a method of treating, preventingand/or managing one or more symptoms associated with arthritis. Examplesof the symptoms include, but are not limited to, joint pain, whichprogresses into joint deformation, or damages in body organs such as inblood vessels, heart, lungs, skin, and muscles.

In one embodiment, provided herein is a method of treating, preventingand/or managing psoriasis. As used herein, “psoriasis” encompasses alltypes and manifestations of psoriasis. Examples include, but are notlimited to, plaque psoriasis (e.g., chronic plaque psoriasis, moderateplaque psoriasis and severe plaque psoriasis), guttate psoriasis,inverse psoriasis, pustular psoriasis, pemphigus vulgaris, erythrodermicpsoriasis, psoriasis associated with inflammatory bowel disease (IBD),and psoriasis associated with rheumatoid arthritis (RA). Also providedherein is a method of treating, preventing and/or managing one or moresymptoms associated with psoriasis. Examples of the symptoms include,but are not limited to: red patches of skin covered with silvery scales;small scaling spots; dry, cracked skin that may bleed; itching; burning;soreness; thickened, pitted or ridged nails; and swollen and stiffjoints.

In one embodiment, provided herein is a method of treating, preventingand/or managing fibrosis and fibrotic condition. As used herein,“fibrosis” or “fibrotic condition encompasses all types andmanifestations of fibrosis or fibrotic condition. Examples include, butare not limited to, formation or deposition of tissue fibrosis; reducingthe size, cellularity (e.g., fibroblast or immune cell numbers),composition; or cellular content, of a fibrotic lesion; reducing thecollagen or hydroxyproline content, of a fibrotic lesion; reducingexpression or activity of a fibrogenic protein; reducing fibrosisassociated with an inflammatory response; decreasing weight lossassociated with fibrosis; or increasing survival.

In certain embodiments, the fibrotic condition is primary fibrosis. Inone embodiment, the fibrotic condition is idiopathic. In otherembodiments, the fibrotic condition is associated with (e.g., issecondary to) a disease (e.g., an infectious disease, an inflammatorydisease, an autoimmune disease, a malignant or cancerous disease, and/ora connective disease); a toxin; an insult (e.g., an environmental hazard(e.g., asbestos, coal dust, polycyclic aromatic hydrocarbons), cigarettesmoking, a wound); a medical treatment (e.g., surgical incision,chemotherapy or radiation), or a combination thereof.

In some embodiments, the fibrotic condition is associated with anautoimmune disease selected from scleroderma or lupus, e.g., systemiclupus erythematosus. In some embodiments, the fibrotic condition issystemic. In some embodiments, the fibrotic condition is systemicsclerosis (e.g., limited systemic sclerosis, diffuse systemic sclerosis,or systemic sclerosis sine scleroderma), nephrogenic systemic fibrosis,cystic fibrosis, chronic graft vs. host disease, or atherosclerosis.

In certain embodiments, the fibrotic condition is a fibrotic conditionof the lung, a fibrotic condition of the liver, a fibrotic condition ofthe heart or vasculature, a fibrotic condition of the kidney, a fibroticcondition of the skin, a fibrotic condition of the gastrointestinaltract, a fibrotic condition of the bone marrow or a hematopoietictissue, a fibrotic condition of the nervous system, a fibrotic conditionof the eye, or a combination thereof.

In other embodiment, the fibrotic condition affects a tissue chosen fromone or more of muscle, tendon, cartilage, skin (e.g., skin epidermis orendodermis), cardiac tissue, vascular tissue (e.g., artery, vein),pancreatic tissue, lung tissue, liver tissue, kidney tissue, uterinetissue, ovarian tissue, neural tissue, testicular tissue, peritonealtissue, colon, small intestine, biliary tract, gut, bone marrow,hematopoietic tissue, or eye (e.g., retinal) tissue.

In some embodiments, the fibrotic condition is a fibrotic condition ofthe eye. In some embodiments, the fibrotic condition is glaucoma,macular degeneration (e.g., age-related macular degeneration), macularedema (e.g., diabetic macular edema), retinopathy (e.g., diabeticretinopathy), or dry eye disease.

In certain embodiments, the fibrotic condition is a fibrotic conditionof the lung. In certain embodiments, the fibrotic condition of the lungis chosen from one or more of: pulmonary fibrosis, idiopathic pulmonaryfibrosis (IPF), usual interstitial pneumonitis (UIP), interstitial lungdisease, cryptogenic fibrosing alveolitis (CFA), bronchiectasis, andscleroderma lung disease. In one embodiment, the fibrosis of the lung issecondary to a disease, a toxin, an insult, a medical treatment, or acombination thereof. For example, the fibrosis of the lung can beassociated with (e.g., secondary to) one or more of: a disease processsuch as asbestosis and silicosis; an occupational hazard; anenvironmental pollutant; cigarette smoking; an autoimmune connectivetissue disorders (e.g., rheumatoid arthritis, scleroderma and systemiclupus erythematosus (SLE)); a connective tissue disorder such assarcoidosis; an infectious disease, e.g., infection, particularlychronic infection; a medical treatment, including but not limited to,radiation therapy, and drug therapy, e.g., chemotherapy (e.g., treatmentwith as bleomycin, methotrexate, amiodarone, busulfan, and/ornitrofurantoin). In one embodiment, the fibrotic condition of the lungtreated with the methods of the invention is associated with (e.g.,secondary to) a cancer treatment, e.g., treatment of a cancer (e.g.,squamous cell carcinoma, testicular cancer, Hodgkin's disease withbleomycin). In one embodiment, the fibrotic condition of the lung isassociated with an autoimmune connective tissue disorder (e.g.,scleroderma or lupus, e.g., SLE).

In certain embodiments, the fibrotic condition is a fibrotic conditionof the liver. In certain embodiments, the fibrotic condition of theliver is chosen from one or more of: fatty liver disease, steatosis(e.g., nonalcoholic steatohepatitis (NASH), cholestatic liver disease(e.g., primary biliary cirrhosis (PBC)), cirrhosis, alcohol inducedliver fibrosis, biliary duct injury, biliary fibrosis, orcholangiopathies. In other embodiments, hepatic or liver fibrosisincludes, but is not limited to, hepatic fibrosis associated withalcoholism, viral infection, e.g., hepatitis (e.g., hepatitis C, B orD), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD),progressive massive fibrosis, exposure to toxins or irritants (e.g.,alcohol, pharmaceutical drugs and environmental toxins).

In certain embodiments, the fibrotic condition is a fibrotic conditionof the heart. In certain embodiments, the fibrotic condition of theheart is myocardial fibrosis (e.g., myocardial fibrosis associated withradiation myocarditis, a surgical procedure complication (e.g.,myocardial post-operative fibrosis), infectious diseases (e.g., Chagasdisease, bacterial, trichinosis or fungal myocarditis)); granulomatous,metabolic storage disorders (e.g., cardiomyopathy, hemochromatosis);developmental disorders (e.g, endocardial fibroelastosis);arteriosclerotic, or exposure to toxins or irritants (e.g., drug inducedcardiomyopathy, drug induced cardiotoxicity, alcoholic cardiomyopathy,cobalt poisoning or exposure). In certain embodiments, the myocardialfibrosis is associated with an inflammatory disorder of cardiac tissue(e.g., myocardial sarcoidosis). In some embodiments, the fibroticcondition is a fibrotic condition associated with a myocardialinfarction. In some embodiments, the fibrotic condition is a fibroticcondition associated with congestive heart failure.

In certain embodiments, the fibrotic condition is a fibrotic conditionof the kidney. In certain embodiments, the fibrotic condition of thekidney is chosen from one or more of: renal fibrosis (e.g., chronickidney fibrosis), nephropathies associated with injury/fibrosis (e.g.,chronic nephropathies associated with diabetes (e.g., diabeticnephropathy)), lupus, scleroderma of the kidney, glomerular nephritis,focal segmental glomerular sclerosis, IgA nephropathyrenal fibrosisassociated with human chronic kidney disease (CKD), chronic progressivenephropathy (CPN), tubulointerstitial fibrosis, ureteral obstruction,chronic uremia, chronic interstitial nephritis, radiation nephropathy,glomerulosclerosis, progressive glomerulonephrosis (PGN),endothelial/thrombotic microangiopathy injury, HIV-associatednephropathy, or fibrosis associated with exposure to a toxin, anirritant, or a chemotherapeutic agent. In one embodiment, the fibroticcondition of the kidney is scleroderma of the kidney. In someembodiments, the fibrotic condition of the kidney is transplantnephropathy, diabetic nephropathy, lupus nephritis, or focal segmentalglomerulosclerosis (FSGS).

In certain embodiments, the fibrotic condition is a fibrotic conditionof the skin. In certain embodiments, the fibrotic condition of the skinis chosen from one or more of: skin fibrosis (e.g., hypertrophicscarring, keloid), scleroderma, nephrogenic systemic fibrosis (e.g.,resulting after exposure to gadolinium (which is frequently used as acontrast substance for MRIs) in patients with severe kidney failure),and keloid.

In certain embodiments, the fibrotic condition is a fibrotic conditionof the gastrointestinal tract. In certain embodiments, the fibroticcondition is chosen from one or more of: fibrosis associated withscleroderma; radiation induced gut fibrosis; fibrosis associated with aforegut inflammatory disorder such as Barrett's esophagus and chronicgastritis, and/or fibrosis associated with a hindgut inflammatorydisorder, such as inflammatory bowel disease (IBD), ulcerative colitisand Crohn's disease. In some embodiments, the fibrotic condition of thegastrointestinal tract is fibrosis associated with scleroderma.

In certain embodiments, the fibrotic condition is a fibrotic conditionof the bone marrow or a hematopoietic tissue. In certain embodiments,the fibrotic condition of the bone marrow is an intrinsic feature of achronic myeloproliferative neoplasm of the bone marrow, such as primarymyelofibrosis (also referred to herein as agnogenic myeloid metaplasiaor chronic idiopathic myelofibrosis). In other embodiments, the bonemarrow fibrosis is associated with (e.g., is secondary to) a malignantcondition or a condition caused by a clonal proliferative disease. Inother embodiments, the bone marrow fibrosis is associated with ahematologic disorder (e.g., a hematologic disorder chosen from one ormore of polycythemia vera, essential thrombocythemia, myelodysplasia,hairy cell leukemia, lymphoma (e.g., Hodgkin or non-Hodgkin lymphoma),multiple myeloma or chronic myelogeneous leukemia (CML)). In yet otherembodiments, the bone marrow fibrosis is associated with (e.g.,secondary to) a non-hematologic disorder (e.g., a non-hematologicdisorder chosen from solid tumor metastasis to bone marrow, anautoimmune disorder (e.g., systemic lupus erythematosus, scleroderma,mixed connective tissue disorder, or polymyositis), an infection (e.g.,tuberculosis), or secondary hyperparathyroidism associated with vitaminD deficiency. In some embodiments, the fibrotic condition is idiopathicor drug-induced myelofibrosis. In some embodiments, the fibroticcondition of the bone marrow or hematopoietic tissue is associated withsystemic lupus erythematosus or scleroderma.

In one embodiment, provided herein is a method of treating, preventingand/or managing scleroderma. Scleroderma is a group of diseases thatinvolve hardening and tightening of the skin and/or other connectivetissues. Scleroderma may be localized (e.g., affecting only the skin) orsystemic (e.g., affecting other systems such as, e.g., blood vesselsand/or internal organs). Common symptoms of scleroderma includeRaynaud's phenomenon, gastroesophageal reflux disease, and skin changes(e.g., swollen fingers and hands, or thickened patches of skin). In someembodiments, the scleroderma is localized, e.g., morphea or linearscleroderma. In some embodiments, the condition is a systemic sclerosis,e.g., limited systemic sclerosis, diffuse systemic sclerosis, orsystemic sclerosis sine scleroderma.

Localized scleroderma (localized cutaneous fibrosis) includes morpheaand linear scleroderma. Morphea is typically characterized byoval-shaped thickened patches of skin that are white in the middle, witha purple border. Linear scleroderma is more common in children. Symptomsof linear scleroderma may appear mostly on one side of the body. Inlinear scleroderma, bands or streaks of hardened skin may develop on oneor both arms or legs or on the forehead. En coup de sabre (frontallinear scleroderma or morphea en coup de sabre) is a type of localizedscleroderma typically characterized by linear lesions of the scalp orface.

Systemic scleroderma (systemic sclerosis) includes, e.g., limitedsystemic sclerosis (also known as limited cutaneous systemic sclerosis,or CREST syndrome), diffuse systemic sclerosis (also known as diffusecutaneous systemic sclerosis), and systemic sclerosis sine scleroderma.CREST stands for the following complications that may accompany limitedscleroderma: calcinosis (e.g., of the digits), Raynaud's phenomenon,esophageal dysfunction, sclerodactyly, and telangiectasias. Typically,limited scleroderma involves cutaneous manifestations that mainly affectthe hands, arms, and face. Limited and diffuse subtypes aredistinguished based on the extent of skin involvement, with sparing ofthe proximal limbs and trunk in limited disease. See, e.g., Denton, C.P. et al. (2006), Nature Clinical Practice Rheumatology, 2(3):134-143.The limited subtype also typically involves a long previous history ofRaynaud's phenomenon, whereas in the diffuse subtype, onset of Raynaud'sphenomenon can be simultaneous with other manifestations or might occurlater. Both limited and diffuse subtypes may involve internal organs.Typical visceral manifestations of limited systemic sclerosis includeisolated pulmonary hypertension, severe bowel involvement, and pulmonaryfibrosis. Typical visceral manifestations of diffuse systemic sclerosisinclude renal crisis, lung fibrosis, and cardiac disease. Diffusesystemic sclerosis typically progresses rapidly and affects a large areaof the skin and one or more internal organs (e.g., kidneys, esophagus,heart, or lungs). Systemic sclerosis sine scleroderma is a rare disorderin which patients develop vascular and fibrotic damage to internalorgans in the absence of cutaneous sclerosis.

In one embodiment, provided herein is a method of treating, preventingand/or managing inflammatory myopathies. As used herein, “inflammatorymyopathies” encompass all types and manifestations of inflammatorymyopathies. Examples include, but are not limited to, muscle weakness(e.g., proximal muscle weakness), skin rash, fatigue after walking orstanding, tripping or falling, dysphagia, dysphonia, difficultybreathing, muscle pain, tender muscles, weight loss, low-grade fever,inflamed lungs, light sensitivity, calcium deposits (calcinosis) underthe skin or in the muscle, as well as biological concomitants ofinflammatory myopathies as disclosed herein or as known in the art.Biological concomitants of inflammatory myopathies (e.g.,dermatomyositis) include, e.g., altered (e.g., increased) levels ofcytokines (e.g., Type I interferons (e.g., IFN-α and/or IFN-β),interleukins (e.g., IL-6, IL-10, IL-15, IL-17 and IL-18), and TNF-α),TGF-β, B-cell activating factor (BAFF), overexpression of IFN induciblegenes (e.g., Type I IFN inducible genes). Other biological concomitantsof inflammatory myopathies can include, e.g., an increased erythrocytesedimentation rate (ESR) and/or elevated level of creatine kinase.Further biological concomitants of inflammatory myopathies can includeautoantibodies, e.g., anti-synthetase autoantibodies (e.g., anti-Jo 1antibodies), anti-signal recognition particle antibodies (anti-SRP),anti-Mi-2 antibodies, anti-p155 antibodies, anti-PM/Sci antibodies, andanti-RNP antibodies.

The inflammatory myopathy can be an acute inflammatory myopathy or achronic inflammatory myopathy. In some embodiments, the inflammatorymyopathy is a chronic inflammatory myopathy (e.g., dermatomyositis,polymyositis, or inclusion body myositis). In some embodiments, theinflammatory myopathy is caused by an allergic reaction, another disease(e.g., cancer or a connective tissue disease), exposure to a toxicsubstance, a medicine, or an infectious agent (e.g., a virus). In someembodiments, the inflammatory myopathy is associated with lupus,rheumatoid arthritis, or systemic sclerosis. In some embodiments, theinflammatory myopathy is idiopathic. In some embodiments, theinflammatory myopathy is selected from polymyositis, dermatomyositis,inclusion body myositis, and immune-mediated necrotizing myopathy. Insome embodiments, the inflammatory myopathy is dermatomyositis.

In another embodiment, provided herein is a method of treating,preventing and/or managing a skin condition (e.g., a dermatitis). Insome embodiments, the methods provided herein can reduce symptomsassociated with a skin condition (e.g., itchiness and/or inflammation).In some such embodiments, the compound provided herein is administeredtopically (e.g., as a topical cream, eyedrop, nose drop or nasal spray).In some such embodiments, the compound is a PI3K delta inhibitor (e.g.,a PI3K inhibitor that demonstrates greater inhibition of PI3K delta thanof other PI3K isoforms). In some embodiments, the PI3K delta inhibitorprevents mast cell degranulation.

As used herein, “skin condition” includes any inflammatory condition ofthe skin (e.g., eczema or dermatitis, e.g., contact dermatitis, atopicdermatitis, dermatitis herpetiformis, seborrheic dermatitis, nummulardermatitis, stasis dermatitis, perioral dermatitis), as well asaccompanying symptoms (e.g., skin rash, itchiness (pruritis), swelling(edema), hay fever, anaphalaxis). Frequently, such skin conditions arecaused by an allergen. As used herein, a “skin condition” also includes,e.g., skin rashes (e.g., allergic rashes, e.g., rashes resulting fromexposure to allergens such as poison ivy, poison oak, or poison sumac,or rashes caused by other diseases or conditions), insect bites, minorburns, sunburn, minor cuts, and scrapes. In some embodiments, thesymptom associated with inflammatory myopathy, or the skin condition orsymptom associated with the skin condition, is a skin rash or itchiness(pruritis) caused by a skin rash.

The skin condition (e.g., the skin rash) may be spontaneous, or it maybe induced, e.g., by exposure to an allergen (e.g., poison ivy, poisonoak, or poison sumac), drugs, food, insect bite, inhalants, emotionalstress, exposure to heat, exposure to cold, or exercise. In someembodiments, the skin condition is a skin rash (e.g., a pruritic rash,e.g., utricaria). In some embodiments, the skin condition is an insectbite. In some embodiments, the skin condition is associated with anotherdisease (e.g., an inflammatory myopathy, e.g., dermatomyositis).

In some embodiments, the subject (e.g., the subject in need of treatmentfor an inflammatory myopathy and/or a skin condition) exhibits anelevated level or elevated activity of IFN-α, TNF-α, IL-6, IL-8, IL-1,or a combination thereof. In certain embodiments, the subject exhibitsan elevated level of IFN-α. In some embodiments, treating (e.g.,decreasing or inhibiting) the inflammatory myopathy, or the skincondition, comprises inhibiting (e.g., decreasing a level of, ordecreasing a biological activity of) one or more of IFN-α, TNF-α, IL-6,IL-8, or IL-1 in the subject or in a sample derived from the subject. Insome embodiments, the method decreases a level of IFN-α, TNF-α, IL-6,IL-8, or IL-1 in the subject or in a sample derived from the subject. Insome embodiments, the method decreases a level of IFN-α in the subjector in a sample derived from the subject. In some embodiments, the levelof IFN-α, TNF-α, IL-6, IL-8, or IL-1 is the level assessed in a sampleof whole blood or PBMCs. In some embodiments, the level of IFN-α, TNF-α,IL-6, IL-8, or IL-1 is the level assessed in a sample obtained by a skinbiopsy or a muscle biopsy. In some embodiments, the sample is obtainedby a skin biopsy.

In one embodiment, provided herein is a method of treating, preventingand/or managing myositis. As used herein, “myositis” encompasses alltypes and manifestations of myositis. Examples include, but are notlimited to, myositis ossificans, fibromyositis, idiopathic inflammatorymyopathies, dermatomyositis, juvenile dermatomyositis, polymyositis,inclusion body myositis and pyomyositis. In one embodiment, the diseaseor disorder is dermatomyositis. Also provided herein is a method oftreating, preventing and/or managing one or more symptoms associatedwith myositis. Examples of the symptoms include, but are not limited to:muscle weakness; trouble lifting arms; trouble swallowing or breathing;muscle pain; muscle tenderness; fatigue; fever; lung problems;gastrointestinal ulcers; intestinal perforations; calcinosis under theskin; soreness; arthritis; weight loss; and rashes.

In one embodiment, provided herein is a method of treating, preventingand/or managing lupus. As used herein, “lupus” refers to all types andmanifestations of lupus. Examples include, but are not limited to,systemic lupus erythematosus; lupus nephritis; cutaneous manifestations(e.g., manifestations seen in cutaneous lupus erythematosus, e.g., askin lesion or rash); CNS lupus; cardiovascular, pulmonary, hepatic,hematological, gastrointestinal and musculoskeletal manifestations;neonatal lupus eythematosus; childhood systemic lupus erythematosus;drug-induced lupus erythematosus; anti-phospholipid syndrome; andcomplement deficiency syndromes resulting in lupus manifestations. Inone embodiment, the lupus is systemic lupus erythematosus (SLE),cutaneous lupus erythematosus (CLE), drug-induced lupus, or neonatallupus. In another embodiment, the lupus is a CLE, e.g., acute cutaneouslupus erythematosus (ACLE), subacute cutaneous lupus erythematosus(SCLE), intermittent cutaneous lupus erythematosus (also known as lupuserythematosus tumidus (LET)), or chronic cutaneous lupus. In someembodiments, the intermittent CLE is chronic discloid lupuserythematosus (CDLE) or lupus erythematosus profundus (LEP) (also knownas lupus erythematosus panniculitis). Types, symptoms, and pathogenesisof CLE are described, for example, in Wenzel et al. (2010), Lupus, 19,1020-1028.

In one embodiment, provided herein is a method of treating, preventingand/or managing Sjögren's syndrome. As used herein, “Sjögren's syndrome”refers to all types and manifestations of Sjögren's syndrome. Examplesinclude, but are not limited to, primary and secondary Sjögren'ssyndrome. Also provided herein is a method of treating, preventingand/or managing one or more symptoms associated with Sjögren's syndrome.Examples of the symptoms include, but are not limited to: dry eyes; drymouth; joint pain; swelling; stiffness; swollen salivary glands; skinrashes; dry skin; vaginal dryness; persistent dry cough; and prolongedfatigue.

In some embodiments, a symptom associated with the disease or disorderprovided herein is reduced by at least 10%, at least 20%, at least 30%,at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, atleast 90%, or at least 95% relative to a control level. The controllevel includes any appropriate control as known in the art. For example,the control level can be the pre-treatment level in the sample orsubject treated, or it can be the level in a control population (e.g.,the level in subjects who do not have the disease or disorder or thelevel in samples derived from subjects who do not have the disease ordisorder). In some embodiments, the decrease is statisticallysignificant, for example, as assessed using an appropriate parametric ornon-parametric statistical comparison.

Combination Therapy

In some embodiments, provided herein are methods for combinationtherapies in which an agent known to modulate other pathways, or othercomponents of the same pathway, or even overlapping sets of targetenzymes are used in combination with a compound as provided herein, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof. In one aspect, such therapy includes, but is notlimited to, the combination of the subject compound withchemotherapeutic agents, therapeutic antibodies, and radiationtreatment, to provide a synergistic or additive therapeutic effect.

In one aspect, a compound as provided herein, or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or pharmaceutical compositions as provided herein, can presentsynergistic or additive efficacy when administered in combination withagents that inhibit IgE production or activity. Such combination canreduce the undesired effect of high level of IgE associated with the useof one or more PI3K-δ inhibitors, if such effect occurs. This can beparticularly useful in treatment of autoimmune and inflammatorydisorders (AIID) such as rheumatoid arthritis. Additionally, theadministration of PI3K-δ or PI3K-δ/γ inhibitors as provided herein incombination with inhibitors of mTOR can also exhibit synergy throughenhanced inhibition of the PI3K pathway.

In a separate but related aspect, provided herein is a combinationtreatment of a disease associated with PI3K-δ comprising administeringto a PI3K-δ inhibitor and an agent that inhibits IgE production oractivity. Other exemplary PI3K-δ inhibitors are applicable for thiscombination and they are described, e.g., U.S. Pat. No. 6,800,620. Suchcombination treatment is particularly useful for treating autoimmune andinflammatory diseases (AIID) including, but not limited to rheumatoidarthritis.

Agents that inhibit IgE production are known in the art and theyinclude, but are not limited to, one or more of TEI-9874,2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid,rapamycin, rapamycin analogs (i.e., rapalogs), TORC1 inhibitors, TORC2inhibitors, and any other compounds that inhibit mTORC1 and mTORC2.Agents that inhibit IgE activity include, for example, anti-IgEantibodies such as for example Omalizumab and TNX-901.

For treatment of autoimmune diseases, a compound as provided herein, ora pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,can be used in combination with commonly prescribed drugs including, butnot limited to Enbrel®, Remicade®, Humira®, Avonex®, and Rebift®. Fortreatment of respiratory diseaseses, the subject compounds orpharmaceutical compositions can be administered in combination withcommonly prescribed drugs including, but not limited to Xolair®,Advair®, Singulair®, and Spiriva®.

The compounds as provided herein, or a pharmaceutically acceptable form(e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein, can be formulated oradministered in conjunction with other agents that act to relieve thesymptoms of inflammatory conditions such as encephalomyelitis, asthma,and the other diseases described herein. These agents includenon-steroidal anti-inflammatory drugs (NSAIDs), e.g., acetylsalicylicacid; ibuprofen; naproxen; indomethacin; nabumetone; tolmetin; etc.Corticosteroids are used to reduce inflammation and suppress activity ofthe immune system. An exemplary drug of this type is Prednisone.Chloroquine (Aralen) or hydroxychloroquine (Plaquenil) can also be usedin some individuals with lupus. They can be prescribed for skin andjoint symptoms of lupus. Azathioprine (Imuran) and cyclophosphamide(Cytoxan) suppress inflammation and tend to suppress the immune system.Other agents, e.g., methotrexate and cyclosporin are used to control thesymptoms of lupus. Anticoagulants are employed to prevent blood fromclotting rapidly. They range from aspirin at very low dose whichprevents platelets from sticking, to heparin/coumadin. Other compoundsused in the treatment of lupus include belimumab (Benlysta®).

In another aspect, provided herein is a pharmaceutical composition forinhibiting abnormal cell growth in a subject which comprises an amountof a compound as provided herein, or a pharmaceutically acceptable form(e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, in combinationwith an amount of an anti-cancer agent (e.g., a chemotherapeutic agent).Many chemotherapeutics are presently known in the art and can be used incombination with the compounds as provided herein.

In some embodiments, the chemotherapeutic is selected from mitoticinhibitors, alkylating agents, anti-metabolites, intercalatingantibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes,topoisomerase inhibitors, biological response modifiers, anti-hormones,angiogenesis inhibitors, and anti-androgens. Non-limiting examples arechemotherapeutic agents, cytotoxic agents, and non-peptide smallmolecules such as Gleevec® (Imatinib Mesylate), Velcade® (bortezomib),Casodex (bicalutamide), Iressa®, and Adriamycin as well as a host ofchemotherapeutic agents. Non-limiting examples of chemotherapeuticagents include alkylating agents such as thiotepa and cyclosphosphamide(CYTOXAN™); alkyl sulfonates such as busulfan, improsulfan andpiposulfan; aziridines such as benzodopa, carboquone, meturedopa, anduredopa; ethylenimines and methylamelamines including altretamine,triethylenemelamine, trietylenephosphoramide,triethylenethiophosphaoramide and trimethylolomelamine; BTK inhibitorssuch as ibrutinib (PCI-32765) and AVL-292; HDAC inhibitors usch asvorinostat, romidepsin, panobinostat, valproic acid, belinostat,mocetinostat, abrexinostat, entinostat, SB939, resminostat, givinostat,CUDC-101, AR-42, CHR-2845, CHR-3996, 4SC-202, CG200745, ACY-1215 andkevetrin; JAK/STAT inhibitors such as lestaurtinib, tofacitinib,ruxolitinib, pacritinib, CYT387, baricitinib, fostamatinib, GLPG0636,TG101348, INCB16562 and AZD1480; nitrogen mustards such as bedamustine,chlorambucil, chlornaphazine, cholophosphamide, estramustine,ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride,melphalan, novembichin, phenesterine, prednimustine, trofosfamide,uracil mustard; nitrosureas such as carmustine, chlorozotocin,fotemustine, lomustine, nimustine, ranimustine; antibiotics such asaclacinomysins, actinomycin, authramycin, azaserine, bleomycins,cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin,Casodex™, chromomycins, dactinomycin, daunorubicin, detorubicin,6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin,olivomycins, peplomycin, potfiromycin, puromycin, quelamycin,rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex,zinostatin, zorubicin; anti-metabolites such as methotrexate and5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pralatrexate, pteropterin, trimetrexate; purine analogssuch as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine;pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine,carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine,floxuridine, androgens such as calusterone, dromostanolone propionate,epitiostanol, mepitiostane, testolactone; anti-adrenals such asaminoglutethimide, mitotane, trilostane; folic acid replenisher such asfrolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinicacid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine;demecolcine; diaziquone; elfomithine; elliptinium acetate; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone;mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK.R™; razoxane;sizofiran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethyla-mine; urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, e.g.,paclitaxel (TAXOL™ Bristol-Myers Squibb Oncology, Princeton, N.J.) anddocetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France) and ABRAXANE®(paclitaxel protein-bound particles); retinoic acid; esperamicins;capecitabine; and pharmaceutically acceptable forms (e.g.,pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) of any of the above.Also included as suitable chemotherapeutic cell conditioners areanti-hormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens including for example tamoxifen(Nolvadex™), raloxifene, aromatase inhibiting 4(5)-imidazoles,4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, andtoremifene (Fareston); and anti-androgens such as flutamide, nilutamide,bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine;6-thioguanine; mercaptopurine; methotrexate; platinum analogs such ascisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16);ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine;navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda;ibandronate; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000;difluoromethylornithine (DMFO). Where desired, the compounds orpharmaceutical composition as provided herein can be used in combinationwith commonly prescribed anti-cancer drugs such as Herceptin®, Avastin®,Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE,Abagovomab, Acridine carboxamide, Adecatumumab,17-N-Allylamino-17-demethoxygeldanamycin, Alpharadin, Alvocidib,3-Aminopyridine-2-carboxaldehyde thiosemicarbazone, Amonafide,Anthracenedione, Anti-CD22 immunotoxins, Antineoplastic, Antitumorigenicherbs, Apaziquone, Atiprimod, Azathioprine, Belotecan, Bendamustine,BIBW 2992, Biricodar, Brostallicin, Bryostatin, Buthionine sulfoximine,CBV (chemotherapy), Calyculin, Crizotinib, cell-cycle nonspecificantineoplastic agents, Dichloroacetic acid, Discodermolide,Elsamitrucin, Enocitabine, Epothilone, Eribulin, Everolimus, Exatecan,Exisulind, Ferruginol, Forodesine, Fosfestrol, ICE chemotherapy regimen,IT-101, Imexon, Imiquimod, Indolocarbazole, Irofulven, Laniquidar,Larotaxel, Lenalidomide, Lucanthone, Lurtotecan, Mafosfamide,Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Ortataxel, PAC-1,Pawpaw, Pixantrone, Proteasome inhibitor, Rebeccamycin, Resiquimod,Rubitecan, SN-38, Salinosporamide A, Sapacitabine, Stanford V,Swainsonine, Talaporfin, Tariquidar, Tegafur-uracil, Temodar, Tesetaxel,Triplatin tetranitrate, Tris(2-chloroethyl)amine, Troxacitabine,Uramustine, Vadimezan, Vinflunine, ZD6126, and Zosuquidar.

In some embodiments, the chemotherapeutic is selected from hedgehoginhibitors including, but not limited to IPI-926 (See U.S. Pat. No.7,812,164). Other suitable hedgehog inhibitors include, for example,those described and provided in U.S. Pat. No. 7,230,004, U.S. PatentApplication Publication No. 2008/0293754, U.S. Patent ApplicationPublication No. 2008/0287420, and U.S. Patent Application PublicationNo. 2008/0293755, the entire disclosures of which are incorporated byreference herein. Examples of other suitable hedgehog inhibitors includethose described in U.S. Patent Application Publication Nos. US2002/0006931, US 2007/0021493 and US 2007/0060546, and InternationalApplication Publication Nos. WO 2001/19800, WO 2001/26644, WO2001/27135, WO 2001/49279, WO 2001/74344, WO 2003/011219, WO2003/088970, WO 2004/020599, WO 2005/013800, WO 2005/033288, WO2005/032343, WO 2005/042700, WO 2006/028958, WO 2006/050351, WO2006/078283, WO 2007/054623, WO 2007/059157, WO 2007/120827, WO2007/131201, WO 2008/070357, WO 2008/110611, WO 2008/112913, and WO2008/131354. Additional examples of hedgehog inhibitors include, but arenot limited to, GDC-0449 (also known as RG3616 or vismodegib) describedin, e.g., Von Hoff D. et al., N. Engl. J. Med. 2009; 361(12):1164-72;Robarge K. D. et al., Bioorg Med Chem Lett. 2009; 19(19):5576-81; Yauch,R. L. et al. (2009) Science 326: 572-574; Sciencexpress: 1-3(10.1126/science.1179386); Rudin, C. et al. (2009) New England J ofMedicine 361-366 (10.1056/nejma0902903); BMS-833923 (also known asXL139) described in, e.g., in Siu L. et al., J. Clin. Oncol. 2010;28:15s (suppl; abstr 2501); and National Institute of Health ClinicalTrial Identifier No. NCT006701891; LDE-225 described, e.g., in Pan S. etal., ACS Med. Chem. Lett., 2010; 1(3): 130-134; LEQ-506 described, e.g.,in National Institute of Health Clinical Trial Identifier No.NCT01106508; PF-04449913 described, e.g., in National Institute ofHealth Clinical Trial Identifier No. NCT00953758; Hedgehog pathwayantagonists provided in U.S. Patent Application Publication No.2010/0286114; SMOi2-17 described, e.g., U.S. Patent ApplicationPublication No. 2010/0093625; SANT-1 and SANT-2 described, e.g., inRominger C. M. et al., J. Pharmacol. Exp. Ther. 2009; 329(3):995-1005;1-piperazinyl-4-arylphthalazines or analogues thereof, described inLucas B. S. et al., Bioorg. Med. Chem. Lett. 2010; 20(12):3618-22.

Other chemotherapeutic agents include, but are not limited to,anti-estrogens (e.g. tamoxifen, raloxifene, and megestrol), LHRHagonists (e.g. goscrclin and leuprolide), anti-androgens (e.g. flutamideand bicalutamide), photodynamic therapies (e.g. vertoporfin (BPD-MA),phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A(2BA-2-DMHA)), nitrogen mustards (e.g. cyclophosphamide, ifosfamide,trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas(e.g. carmustine (BCNU) and lomustine (CCNU)), alkylsulphonates (e.g.busulfan and treosulfan), triazenes (e.g. dacarbazine, temozolomide),platinum containing compounds (e.g. cisplatin, carboplatin,oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine,and vinorelbine), taxoids (e.g. paclitaxel or a paclitaxel equivalentsuch as nanoparticle albumin-bound paclitaxel (Abraxane),docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin),polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex,CT-2103, XYOTAX), the tumor-activated prodrug (TAP) ANG1005 (Angiopep-2bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxelbound to the erbB2-recognizing peptide EC-1), and glucose-conjugatedpaclitaxel, e.g., 2′-paclitaxel methyl 2-glucopyranosyl succinate;docetaxel, taxol), epipodophyllins (e.g. etoposide, etoposide phosphate,teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan,irinotecan, crisnatol, mytomycin C), anti-metabolites, DHFR inhibitors(e.g. methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMPdehydrogenase inhibitors (e.g. mycophenolic acid, tiazofurin, ribavirin,and EICAR), ribonuclotide reductase inhibitors (e.g. hydroxyurea anddeferoxamine), uracil analogs (e.g. 5-fluorouracil (5-FU), floxuridine,doxifluridine, ratitrexed, tegafur-uracil, capecitabine), cytosineanalogs (e.g. cytarabine (ara C), cytosine arabinoside, andfludarabine), purine analogs (e.g. mercaptopurine and Thioguanine),Vitamin D3 analogs (e.g. EB 1089, CB 1093, and KH 1060), isoprenylationinhibitors (e.g. lovastatin), dopaminergic neurotoxins (e.g.1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g.staurosporine), actinomycin (e.g. actinomycin D, dactinomycin),bleomycin (e.g. bleomycin A2, bleomycin B2, peplomycin), anthracycline(e.g. daunorubicin, doxorubicin, pegylated liposomal doxorubicin,idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDRinhibitors (e.g. verapamil), Ca2+ ATPase inhibitors (e.g. thapsigargin),imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g.,axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN™,AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®),gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib(TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272),nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®,SU11248), toceranib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474),vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN®), bevacizumab(AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab(VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib(NEXAVAR®), everolimus (AFINITOR®), alemtuzumab (CAMPATH®), gemtuzumabozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD-2076, PCI-32765,AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK™), SGX523,PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154,CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and/orXL228), proteasome inhibitors (e.g., bortezomib (Velcade)), mTORinhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus(RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235(Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502(Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)),oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed,cyclophosphamide, dacarbazine, procarbizine, prednisolone,dexamethasone, campathecin, plicamycin, asparaginase, aminopterin,methopterin, porfiromycin, melphalan, leurosidine, leurosine,chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin,aminopterin, and hexamethyl melamine.

Exemplary biotherapeutic agents include, but are not limited to,interferons, cytokines (e.g., tumor necrosis factor, interferon α,interferon γ), vaccines, hematopoietic growth factors, monoclonalserotherapy, immunostimulants and/or immunodulatory agents (e.g., IL-1,2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) andantibodies (e.g. Herceptin (trastuzumab), T-DM1, AVASTIN (bevacizumab),ERBITUX (cetuximab), Vectibix (panitumumab), Rituxan (rituximab), Bexxar(tositumomab)).

In some embodiments, the chemotherapeutic is selected from HSP90inhibitors. The HSP90 inhibitor can be a geldanamycin derivative, e.g.,a benzoquinone or hygroquinone ansamycin HSP90 inhbitor (e.g., IPI-493and/or IPI-504). Non-limiting examples of HSP90 inhibitors includeIPI-493, IPI-504, 17-AAG (also known as tanespimycin or CNF-1010),BIIB-021 (CNF-2024), BIIB-028, AUY-922 (also known as VER-49009),SNX-5422, STA-9090, AT-13387, XL-888, MPC-3100, CU-0305, 17-DMAG,CNF-1010, Macbecin (e.g., Macbecin I, Macbecin II), CCT-018159,CCT-129397, PU-H71, or PF-04928473 (SNX-2112).

In some embodiments, the chemotherapeutic is selected from PI3Kinhibitors (e.g., including those PI3K inhibitors provided herein andthose PI3K inhibitors not provided herein). In some embodiment, the PI3Kinhibitor is an inhibitor of delta and gamma isoforms of PI3K. In someembodiments, the PI3K inhibitor is an inhibitor of alpha isoforms ofPI3K. In other embodiments, the PI3K inhibitor is an inhibitor of one ormore alpha, beta, delta and gamma isoforms of PI3K. Exemplary PI3Kinhibitors that can be used in combination are described in, e.g., WO09/088990, WO 09/088086, WO 2011/008302, WO 2010/036380, WO 2010/006086,WO 09/114870, WO 05/113556; US 2009/0312310, and US 2011/0046165.Additional PI3K inhibitors that can be used in combination with thepharmaceutical compositions, include but are not limited to, AMG-319,GSK 2126458, GDC-0980, GDC-0941, Sanofi XL147, XL499, XL756, XL147,PF-46915032, BKM 120, CAL-101 (GS-1101), CAL 263, SF1126, PX-886, and adual PI3K inhibitor (e.g., Novartis BEZ235). In one embodiment, the PI3Kinhibitor is an isoquinolinone.

In some embodiments, provided herein is a method for using the acompound as provided herein, or a pharmaceutically acceptable form(e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein, in combination withradiation therapy in inhibiting abnormal cell growth or treating thehyperproliferative disorder in the subject. Techniques for administeringradiation therapy are known in the art, and these techniques can be usedin the combination therapy described herein. The administration of thecompound as provided herein in this combination therapy can bedetermined as described herein.

Radiation therapy can be administered through one of several methods, ora combination of methods, including without limitation external-beamtherapy, internal radiation therapy, implant radiation, stereotacticradiosurgery, systemic radiation therapy, radiotherapy and permanent ortemporary interstitial brachytherapy. The term “brachytherapy,” as usedherein, refers to radiation therapy delivered by a spatially confinedradioactive material inserted into the body at or near a tumor or otherproliferative tissue disease site. The term is intended withoutlimitation to include exposure to radioactive isotopes (e.g., At-211,I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, andradioactive isotopes of Lu). Suitable radiation sources for use as acell conditioner as provided herein include both solids and liquids. Byway of non-limiting example, the radiation source can be a radionuclide,such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solidsource, or other radionuclides that emit photons, beta particles, gammaradiation, or other therapeutic rays. The radioactive material can alsobe a fluid made from any solution of radionuclide(s), e.g., a solutionof I-125 or I-131, or a radioactive fluid can be produced using a slurryof a suitable fluid containing small particles of solid radionuclides,such as Au-198, Y-90. Moreover, the radionuclide(s) can be embodied in agel or radioactive micro spheres.

Without being limited by any theory, the compounds as provided herein,or a pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,can render abnormal cells more sensitive to treatment with radiation forpurposes of killing and/or inhibiting the growth of such cells.Accordingly, provided herein is a method for sensitizing abnormal cellsin a subject to treatment with radiation which comprises administeringto the subject an amount of a compound as provided herein orpharmaceutically acceptable forms (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, which amount is effective is sensitizing abnormalcells to treatment with radiation. The amount of the compound used inthis method can be determined according to the means for ascertainingeffective amounts of such compounds described herein.

The compounds as provided herein, or a pharmaceutically acceptable form(e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein, can be used incombination with an amount of one or more substances selected fromanti-angiogenesis agents, signal transduction inhibitors, andantiproliferative agents, glycolysis inhibitors, or autophagyinhibitors.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloproteinase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-11(cyclooxygenase 11) inhibitors, can be used in conjunction with acompound as provided herein and pharmaceutical compositions describedherein. Anti-angiogenesis agents include, for example, rapamycin,temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, andbevacizumab. Examples of useful COX-II inhibitors include CELEBREX™(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrixmetalloproteinase inhibitors are described in WO 96/33172 (publishedOct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), European PatentApplication No. 97304971.1 (filed Jul. 8, 1997), European PatentApplication No. 99308617.2 (filed Oct. 29, 1999), WO 98/07697 (publishedFeb. 26, 1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918(published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998), WO98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul. 16,1998), European Patent Publication 606,046 (published Jul. 13, 1994),European Patent Publication 931, 788 (published Jul. 28, 1999), WO90/05719 (published May 31, 1990), WO 99/52910 (published Oct. 21,1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667 (publishedJun. 17, 1999), PCT International Application No. PCT/IB98/01113 (filedJul. 21, 1998), European Patent Application No. 99302232.1 (filed Mar.25, 1999), Great Britain Patent Application No. 9912961.1 (filed Jun. 3,1999), U.S. Provisional Application No. 60/148,464 (filed Aug. 12,1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No.5,861,510 (issued Jan. 19, 1999), and European Patent Publication780,386 (published Jun. 25, 1997), all of which are incorporated hereinin their entireties by reference. In some embodiments, MMP-2 and MMP-9inhibitors are those that have little or no activity inhibiting MMP-1.Other embodiments include those that selectively inhibit MMP-2 and/orAMP-9 relative to the other matrix-metalloproteinases (i.e., MAP-1,MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, andMMP-13). Some non-limiting examples of MMP inhibitors are AG-3340, RO32-3555, and RS 13-0830.

Autophagy inhibitors include, but are not limited to, chloroquine,3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1,5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid,autophagy-suppressive algal toxins which inhibit protein phosphatases oftype 2A or type 1, analogues of cAMP, and drugs which elevate cAMPlevels such as adenosine, LY204002, N6-mercaptopurine riboside, andvinblastine. In addition, antisense or siRNA that inhibits expression ofproteins including, but not limited to ATG5 (which are implicated inautophagy), can also be used.

In some embodiments, provided herein is a method of and/or apharmaceutical composition for treating a cardiovascular disease in asubject which comprises an amount of a compound as provided herein, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, and an amount of one or more therapeutic agentsuse for the treatment of cardiovascular diseases.

Exemplary agents for use in cardiovascular disease applications areanti-thrombotic agents, e.g., prostacyclin and salicylates, thrombolyticagents, e.g., streptokinase, urokinase, tissue plasminogen activator(TPA) and anisoylated plasminogen-streptokinase activator complex(APSAC), anti-platelets agents, e.g., acetyl-salicylic acid (ASA) andclopidrogel, vasodilating agents, e.g., nitrates, calcium channelblocking drugs, anti-proliferative agents, e.g., colchicine andalkylating agents, intercalating agents, growth modulating factors suchas interleukins, transformation growth factor-beta and congeners ofplatelet derived growth factor, monoclonal antibodies directed againstgrowth factors, anti-inflammatory agents, both steroidal andnon-steroidal, and other agents that can modulate vessel tone, function,arteriosclerosis, and the healing response to vessel or organ injurypost intervention. Antibiotics can also be included in combinations orcoatings. Moreover, a coating can be used to effect therapeutic deliveryfocally within the vessel wall. By incorporation of the active agent ina swellable polymer, the active agent will be released upon swelling ofthe polymer.

The compounds as provided herein, or a pharmaceutically acceptable form(e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein, can be formulated oradministered in conjunction with liquid or solid tissue barriers alsoknown as lubricants. Examples of tissue barriers include, but are notlimited to, polysaccharides, polyglycans, seprafilm, interceed andhyaluronic acid.

Medicaments which can be administered in conjunction with the compoundsas provided herein, or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, include anysuitable drugs usefully delivered by inhalation for example, analgesics,e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine;anginal preparations, e.g., diltiazem; antiallergics, e.g. cromoglycate,ketotifen or nedocromil; anti-infectives, e.g., cephalosporins,penicillins, streptomycin, sulphonamides, tetracyclines or pentamidine;antihistamines, e.g., methapyrilene; anti-inflammatories, e.g.,beclomethasone, flunisolide, budesonide, tipredane, triamcinoloneacetonide or fluticasone; antitussives, e.g., noscapine;bronchodilators, e.g., ephedrine, adrenaline, fenoterol, formoterol,isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine,pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutalin,isoetharine, tulobuterol, orciprenaline or(−)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol;diuretics, e.g., amiloride; anticholinergics e.g., ipratropium, atropineor oxitropium; hormones, e.g., cortisone, hydrocortisone orprednisolone; xanthines e.g., aminophylline, choline theophyllinate,lysine theophyllinate or theophylline; and therapeutic proteins andpeptides, e.g., insulin or glucagon. It will be clear to a personskilled in the art that, where appropriate, the medicaments can be usedin the form of salts (e.g., as alkali metal or amine salts or as acidaddition salts) or as esters (e.g., lower alkyl esters) to optimize theactivity and/or stability of the medicament.

Other exemplary therapeutic agents useful for a combination therapyinclude, but are not limited to, agents as described above, radiationtherapy, hormone antagonists, hormones and their releasing factors,thyroid and antithyroid drugs, estrogens and progestins, androgens,adrenocorticotropic hormone; adrenocortical steroids and their syntheticanalogs; inhibitors of the synthesis and actions of adrenocorticalhormones, insulin, oral hypoglycemic agents, and the pharmacology of theendocrine pancreas, agents affecting calcification and bone turnover:calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitaminssuch as water-soluble vitamins, vitamin B complex, ascorbic acid,fat-soluble vitamins, vitamins A, K, and E, growth factors, cytokines,chemokines, muscarinic receptor agonists and antagonists;anticholinesterase agents; agents acting at the neuromuscular junctionand/or autonomic ganglia; catecholamines, sympathomimetic drugs, andadrenergic receptor agonists or antagonists; and 5-hydroxytryptamine(5-HT, serotonin) receptor agonists and antagonists.

Therapeutic agents can also include agents for pain and inflammationsuch as histamine and histamine antagonists, bradykinin and bradykininantagonists, 5-hydroxytryptamine (serotonin), lipid substances that aregenerated by biotransformation of the products of the selectivehydrolysis of membrane phospholipids, eicosanoids, prostaglandins,thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatoryagents, analgesic-antipyretic agents, agents that inhibit the synthesisof prostaglandins and thromboxanes, selective inhibitors of theinducible cyclooxygenase, selective inhibitors of the induciblecyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin,cytokines that mediate interactions involved in humoral and cellularimmune responses, lipid-derived autacoids, eicosanoids, β-adrenergicagonists, ipratropium, glucocorticoids, methylxanthines, sodium channelblockers, opioid receptor agonists, calcium channel blockers, membranestabilizers and leukotriene inhibitors.

Additional therapeutic agents contemplated herein include diuretics,vasopressin, agents affecting the renal conservation of water, rennin,angiotensin, agents useful in the treatment of myocardial ischemia,anti-hypertensive agents, angiotensin converting enzyme inhibitors,B3-adrenergic receptor antagonists, agents for the treatment ofhypercholesterolemia, and agents for the treatment of dyslipidemia.

Other therapeutic agents contemplated herein include drugs used forcontrol of gastric acidity, agents for the treatment of peptic ulcers,agents for the treatment of gastroesophageal reflux disease, prokineticagents, antiemetics, agents used in irritable bowel syndrome, agentsused for diarrhea, agents used for constipation, agents used forinflammatory bowel disease, agents used for biliary disease, agents usedfor pancreatic disease. Therapeutic agents include, but are not limitedto, those used to treat protozoan infections, drugs used to treatMalaria, Amebiasis, Giardiasis, Trichomoniasis, Trypanosomiasis, and/orLeishmaniasis, and/or drugs used in the chemotherapy of helminthiasis.Other therapeutic agents include, but are not limited to, antimicrobialagents, sulfonamides, trimethoprim-sulfamethoxazole quinolones, andagents for urinary tract infections, penicillins, cephalosporins, andother, β-Lactam antibiotics, an agent containing an aminoglycoside,protein synthesis inhibitors, drugs used in the chemotherapy oftuberculosis, mycobacterium avium complex disease, and leprosy,antifungal agents, antiviral agents including nonretroviral agents andantiretroviral agents.

Examples of therapeutic antibodies that can be combined with a subjectcompound include but are not limited to anti-receptor tyrosine kinaseantibodies (cetuximab, panitumumab, trastuzumab), anti CD20 antibodies(rituximab, tositumomab), and other antibodies such as alemtuzumab,bevacizumab, and gemtuzumab.

Moreover, therapeutic agents used for immunomodulation, such asimmunomodulators, immunosuppressive agents, tolerogens, andimmunostimulants are contemplated by the methods herein. In addition,therapeutic agents acting on the blood and the blood-forming organs,hematopoietic agents, growth factors, minerals, and vitamins,anticoagulant, thrombolytic, and antiplatelet drugs.

For treating renal carcinoma, one can combine a compound as providedherein, or a pharmaceutically acceptable form (e.g., pharmaceuticallyacceptable salts, hydrates, solvates, isomers, prodrugs, andisotopically labeled derivatives) thereof, or pharmaceuticalcompositions as provided herein, with sorafenib and/or avastin. Fortreating an endometrial disorder, one can combine a compound as providedherein with doxorubincin, taxotere (taxol), and/or cisplatin(carboplatin). For treating ovarian cancer, one can combine a compoundas provided herein with cisplatin (carboplatin), taxotere, doxorubincin,topotecan, and/or tamoxifen. For treating breast cancer, one can combinea compound as provided herein with taxotere (taxol), gemcitabine(capecitabine), tamoxifen, letrozole, tarceva, lapatinib, PD0325901,avastin, herceptin, OSI-906, and/or OSI-930. For treating lung cancer,one can combine a compound as provided herein with taxotere (taxol),gemcitabine, cisplatin, pemetrexed, Tarceva, PD0325901, and/or avastin.

In some embodiments, the disorder to be treated, prevented and/ormanaged is hematological cancer, e.g., lymphoma (e.g., T-cell lymphoma;NHL), myeloma (e.g., multiple myeloma), and leukemia (e.g., CLL), and acompound provided herein is used in combination with: HDAC inhibitorssuch as vorinostat and romidepsin; mTOR inhibitors such as everolmus;anti-folates such as pralatrexate; nitrogen mustard such asbendamustine; gemcitabine, optionally in further combination withoxaliplatin; rituximab.cyclophosphamide combination; PI3K inhibitorssuch as GS-1101, XL 499, GDC-0941, and AMG-319; or BTK inhibitors suchas ibrutinib and AVL-292.

In certain embodiments, wherein inflammation (e.g., arthritis, asthma)is treated, prevented and/or managed, a compound provided herein can becombined with, for example: PI3K inhibitors such as GS-1101, XL 499,GDC-0941, and AMG-319; BTK inhibitors such as ibrutinib and AVL-292; JAKinhibitors such as tofacitinib, fostamatinib, and GLPG0636.

In certain embodiments wherein asthma is treated, prevented and/ormanaged, a compound provided herein can be combined with, for example:beta 2-agonists such as, but not limited to, albuterol (Proventil®, orVentolin®), salmeterol (Serevent®), formoterol (Foradil®),metaproterenol (Alupent®), pirbuterol (MaxAir®), and terbutalinesulfate; corticosteroids such as, but not limited to, budesonide (e.g.,Pulmicort®), flunisolide (e.g., AeroBid Oral Aerosol Inhaler® orNasalide Nasal Aerosol®), fluticasone (e.g., Flonase® or Flovent®) andtriamcinolone (e.g., Azmacort®); mast cell stabilizers such as cromolynsodium (e.g., Intal® or Nasalcrom®) and nedocromil (e.g., Tilade®);xanthine derivatives such as, but not limited to, theophylline (e.g.,Aminophyllin®, Theo-24® or Theolair®); leukotriene receptor antagonistssuch as, but are not limited to, zafirlukast (Accolate®), montelukast(Singulair®), and zileuton (Zyflo®); and adrenergic agonists such as,but are not limited to, epinephrine (Adrenalin®, Bronitin®, EpiPen® orPrimatene Mist®).

In certain embodiments wherein arthritis is treated, prevented and/ormanaged, a compound provided herein can be combined with, for example:TNF antagonist (e.g., a TNF antibody or fragment, a soluble TNF receptoror fragment, fusion proteins thereof, or a small molecule TNFantagonist); an antirheumatic (e.g., methotrexate, auranofin,aurothioglucose, azathioprine, etanercept, gold sodium thiomalate,hydroxychloroquine sulfate, leflunomide, sulfasalzine); a musclerelaxant; a narcotic; a non-steroid anti-inflammatory drug (NSAID); ananalgesic; an anesthetic; a sedative; a local anesthetic; aneuromuscular blocker; an antimicrobial (e.g., an aminoglycoside, anantifungal, an antiparasitic, an antiviral, a carbapenem, cephalosporin,a fluoroquinolone, a macrolide, a penicillin, a sulfonamide, atetracycline, another antimicrobial); an antipsoriatic; acorticosteroid; an anabolic steroid; a cytokine or a cytokineantagonist.

In certain embodiments wherein psoriasis is treated, prevented and/ormanaged, a compound provided herein can be combined with, for example:budesonide, epidermal growth factor, corticosteroids, cyclosporine,sulfasalazine, aminosalicylates, 6-mercaptopurine, azathioprine,metronidazole, lipoxygenase inhibitors, mesalamine, olsalazine,balsalazide, antioxidants, thromboxane inhibitors, IL-1 receptorantagonists, anti-IL-1β monoclonal antibodies, anti-IL-6 monoclonalantibodies, growth factors, elastase inhibitors, pyridinyl-imidazolecompounds, antibodies or agonists of TNF, LT, IL-1, IL-2, IL-6, IL-7,IL-8, IL-15, IL-16, IL-18, EMAP-II, GM-CSF, FGF, and PDGF, antibodies ofCD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or theirligands, methotrexate, cyclosporine, FK506, rapamycin, mycophenolatemofetil, leflunomide, NSAIDs, ibuprofen, corticosteroids, prednisolone,phosphodiesterase inhibitors, adenosine agonists, antithrombotic agents,complement inhibitors, adrenergic agents, IRAK, NIK, IKK, p38, MAPkinase inhibitors, IL-1β converting enzyme inhibitors, TNFα convertingenzyme inhibitors, T-cell signaling inhibitors, metalloproteinaseinhibitors, sulfasalazine, azathioprine, 6-mercaptopurines, angiotensinconverting enzyme inhibitors, soluble cytokine receptors, soluble p55TNF receptor, soluble p75 TNF receptor, sIL-1RI, sIL-1RII, sIL-6R,anti-inflammatory cytokines, IL-4, IL-10, IL-11, IL-13 and TGFβ.

In certain embodiments wherein fibrosis or fibrotic condition of thebone marrow is treated, prevented and/or managed, a compound providedherein can be combined with, for example, a Jak2 inhibitor (including,but not limited to, INCB018424, XL019, TG101348, or TG101209), animmunomodulator, e.g., an IMID® (including, but not limited tothalidomide, lenalidomide, or panolinomide), hydroxyurea, an androgen,erythropoietic stimulating agents, prednisone, danazol, HDAC inhibitors,or other agents or therapeutic modalities (e.g., stem cell transplants,or radiation).

In certain embodiments wherein fibrosis or fibrotic condition of theheart is treated, prevented and/or managed, a compound provided hereincan be combined with, for example, eplerenone, furosemide, pycnogenol,spironolactone, TcNC100692, torasemide (e.g., prolonged release form oftorasemide), or combinations thereof.

In certain embodiments wherein fibrosis or fibrotic condition of thekidney is treated, prevented and/or managed, a compound provided hereincan be combined with, for example, cyclosporine, cyclosporine A,daclizumab, everolimus, gadofoveset trisodium (ABLAVAR®), imatinibmesylate (GLEEVEC®), matinib mesylate, methotrexate, mycophenolatemofetil, prednisone, sirolimus, spironolactone, STX-100, tamoxifen,TheraCLEC™, or combinations thereof.

In certain embodiments wherein fibrosis or fibrotic condition of theskin is treated, prevented and/or managed, a compound provided hereincan be combined with, for example, Bosentan (Tracleer), p144,pentoxifylline; pirfenidone; pravastatin, STI571, Vitamin E, orcombinations thereof.

In certain embodiments wherein fibrosis or fibrotic condition of thegastrointestinal system is treated, prevented and/or managed, a compoundprovided herein can be combined with, for example, ALTU-135, bucelipasealfa (INN), DCI1020, EUR-1008 (ZENPEP™), ibuprofen, Lym-X-Sorb powder,pancrease MT, pancrelipase (e.g., pancrelipase delayed release), pentadecanoic acid (PA), repaglinide, TheraCLEC™, triheptadecanoin (THA),ULTRASE MT20, ursodiol, or combinations thereof.

In certain embodiments wherein fibrosis or fibrotic condition of thelung is treated, prevented and/or managed, a compound provided hereincan be combined with, for example, 18-FDG, AB0024, ACT-064992(macitentan), aerosol interferon-gamma, aerosolized human plasma-derivedalpha-1 antitrypsin, alphal-proteinase inhibitor, ambrisentan, amikacin,amiloride, amitriptyline, anti-pseudomonas IgY gargle, ARIKACE™,AUREXIS® (tefibazumab), AZAPRED, azathioprine, azithromycin,azithromycin, AZLI, aztreonam lysine, BIBF1120, Bio-25 probiotic,bosentan, Bramitob®, calfactant aerosol, captopril, CC-930, ceftazidime,ceftazidime, cholecalciferol (Vitamin D3), ciprofloxacin (CIPRO®,BAYQ3939), CNTO 888, colistin CF, combined Plasma Exchange (PEX),rituximab, and corticosteroids, cyclophosphamide, dapsone, dasatinib,denufosol tetrasodium (INS37217), dornase alfa (PULMOZYME®), EPI-hNE4,erythromycin, etanercept, FG-3019, fluticasone, FTI, GC1008, GS-9411,hypertonic saline, ibuprofen, iloprost inhalation, imatinib mesylate(GLEEVEC®), inhaled sodium bicarbonate, inhaled sodium pyruvate,interferon gamma-lb, interferon-alpha lozenges, isotonic saline, IW001,KB001, losartan, lucinactant, mannitol, meropenem, meropenem infusion,miglustat, minocycline, Moli1901, MP-376 (levofloxacin solution forinhalation), mucoid exopolysaccharide P. aeruginosa immune globulin IV,mycophenolate mofetil, n-acetylcysteine, N-acetylcysteine (NAC), NaCl6%, nitric oxide for inhalation, obramycin, octreotide, oligoG CF-5/20,Omalizumab, pioglitazone, piperacillin-tazobactam, pirfenidone,pomalidomide (CC-4047), prednisone, prevastatin, PRM-151, QAX576,rhDNAse, SB656933, SB-656933-AAA, sildenafil, tamoxifen, technetium[Tc-99m] sulfur colloid and Indium [In-111] DTPA, tetrathiomolybdate,thalidomide, ticarcillin-clavulanate, tiotropium bromide, tiotropiumRESPIMAT® inhaler, tobramycin (GERNEBCIN®), treprostinil, uridine,valganciclovir (VALCYTE®), vardenafil, vitamin D3, xylitol, zileuton, orcombinations thereof.

In certain embodiments wherein fibrosis or fibrotic condition of theliver is treated, prevented and/or managed, a compound provided hereincan be combined with, for example, adefovir dipivoxil, candesartan,colchicine, combined ATG, mycophenolate mofetil, and tacrolimus,combined cyclosporine microemulsion and tacrolimus, elastometry,everolimus, FG-3019, Fuzheng Huayu, GI1262570, glycyrrhizin(monoammonium glycyrrhizinate, glycine, L-cysteine monohydrochloride),interferon gamma-1b, irbesartan, losartan, oltipraz, ORAL IMPACT®,peginterferon alfa-2a, combined peginterferon alfa-2a and ribavirin,peginterferon alfa-2b (SCH 54031), combined peginterferon alpha-2b andribavirin, praziquantel, prazosin, raltegravir, ribavirin (REBETOL®, SCH18908), ritonavir-boosted protease inhibitor, pentoxyphilline,tacrolimus, tauroursodeoxycholic acid, tocopherol, ursodiol, warfarin,or combinations thereof.

In certain embodiments wherein cystic fibrosis is treated, preventedand/or managed, a compound provided herein can be combined with, forexample, 552-02, 5-methyltetrahydrofolate and vitamin B12, Ad5-CB-CFTR,Adeno-associated virus-CFTR vector, albuterol, alendronate, alphatocopherol plus ascorbic acid, amiloride HCl, aquADEK™, ataluren(PTC124), AZD1236, AZD9668, azithromycin, bevacizumab, biaxin(clarithromycin), BIIL 283 BS (amelubent), buprofen, calcium carbonate,ceftazidime, cholecalciferol, choline supplementation, CPX, cysticfibrosis transmembrane conductance regulator, DHA-rich supplement,digitoxin, cocosahexaenoic acid (DHA), doxycycline, ECGC, ecombinanthuman IGF-1, educed glutathione sodium salt, ergocalciferol (vitaminD2), fluorometholone, gadobutrol (GADOVIST®, BAY86-4875), gentamicin,ghrelin, glargine, glutamine, growth hormone, GS-9411, H5.001CBCFTR,human recombinant growth hormone, hydroxychloroquine, hyperbaric oxygen,hypertonic saline, IH636 grape seed proanthocyanidin extract, insulin,interferon gamma-lb, IoGen (molecular iodine), iosartan potassium,isotonic saline, itraconazole, IV gallium nitrate (GANITE®) infusion,ketorolac acetate, lansoprazole, L-arginine, linezolid, lubiprostone,meropenem, miglustat, MP-376 (levofloxacin solution for inhalation),normal saline IV, Nutropin AQ, omega-3 triglycerides, pGM169/GL67A,pGT-1 gene lipid complex, pioglitazone, PTC124, QAU145, salmeterol,SB656933, SB656933, simvastatin, sitagliptin, sodium 4-phenylbutyrate,standardized turmeric root extract, tgAAVCF, TNF blocker, TOBI,tobramycin, tocotrienol, unconjugated Isoflavones 100, vitamin: cholinebitartrate (2-hydroxyethyl) trimethylammonium salt 1:1, VX-770, VX-809,Zinc acetate, or combinations thereof.

In some embodiments, a compound provided herein is administered incombination with an agent that inhibits IgE production or activity. Insome embodiments, the PI3K inhibitor (e.g., PI3Kδ inhibitor) isadministered in combination with an inhibitor of mTOR. Agents thatinhibit IgE production are known in the art and they include but are notlimited to one or more of TEI-9874,2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid,rapamycin, rapamycin analogs (i.e. rapalogs), TORC1 inhibitors, TORC2inhibitors, and any other compounds that inhibit mTORC1 and mTORC2.Agents that inhibit IgE activity include, for example, anti-IgEantibodies such as for example Omalizumab and TNX-901.

In certain embodiments wherein scleroderma is treated, prevented and/ormanaged, a compound provided herein can be combined with, for example:an immunosuppressant (e.g., methotrexate, azathioprine (Imuran®),cyclosporine, mycophenolate mofetil (Cellcept®), and cyclophosphamide(Cytoxan®)); T-cell-directed therapy (e.g., halofuginone, basiliximab,alemtuzumab, abatacept, rapamycin); B-cell directed therapy (e.g.,rituximab); autologous hematopoietic stem cell transplantation; achemokine ligand receptor antagonist (e.g., an agent that targets theCXCL12/CSCR4 axis (e.g., AMD3100)); a DNA methylation inhibitor (e.g.,5-azacytidine); a histone dactylase inhibitor (e.g., trichostatin A); astatin (e.g., atorvastatin, simvastatin, pravastatin); an endothelinreceptor antagonist (e.g., Bosentan®); a phosphodiesterase type Vinhibitor (e.g., Sildenafil®); a prostacyclin analog (e.g.,trepostinil); an inhibitor of cytokine synthesis and/or signaling (e.g.,Imatinib mesylate, Rosiglitazone, rapamycin, antitransforming growthfactor β1 (anti-TGFβ1) antibody, mycophenolate mofetil, an anti-IL-6antibody (e.g., tocilizumab)); corticosteroids; nonsteroidalanti-inflammatory drugs; light therapy; and blood pressure medications(e.g., ACE inhibitors).

In certain embodiments wherein inflammatory myopathies are treated,prevented and/or managed, a compound provided herein can be combinedwith, for example: topical creams or ointments (e.g., topicalcorticosteroids, tacrolimus, pimecrolimus); cyclosporine (e.g., topicalcyclosporine); an anti-interferon therapy, e.g., AGS-009, Rontalizumab(rhuMAb IFNalpha), Vitamin D3, Sifalimumab (MEDI-545), AMG 811, IFNαKinoid, or CEP33457. In some embodiments, the other therapy is an IFN-αtherapy, e.g., AGS-009, Rontalizumab, Vitamin D3, Sifalimumab (MEDI-545)or IFNα Kinoid; corticosteroids such as prednisone (e.g., oralprednisone); immunosuppressive therapies such as methotrexate (Trexall®,Methotrexate®, Rheumatrex®), azathioprine (Azasan®, Imuran®),intravenous immunoglobulin, tacrolimus (Prograf®), pimecrolimus,cyclophosphamide (Cytoxan®), and cyclosporine (Gengraf®, Neoral®,Sandimmune®); anti-malarial agents such as hydroxychloroquine(Plaquenil®) and chloroquine (Aralen®); total body irradiation;rituximab (Rituxan®); TNF inhibitors (e.g., etanercept (Enbrel®),infliximab (Remicade®)); AGS-009; Rontalizumab (rhuMAb IFNalpha);Vitamin D3; Sifalimumab (MEDI-545); AMG 811; IFNα Kinoid; CEP33457;agents that inhibit IgE production such as TEI-9874,2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid,rapamycin, rapamycin analogs (i.e. rapalogs), TORC1 inhibitors, TORC2inhibitors, and any other compounds that inhibit mTORC1 and mTORC2;agents that inhibit IgE activity such as anti-IgE antibodies (e.g.,Omalizumab and TNX-90); and additional therapies such as physicaltherapy, exercise, rest, speech therapy, sun avoidance, heat therapy,and surgery.

In certain embodiments wherein myositis (e.g., dermatomysitis) istreated, prevented and/or managed, a compound provided herein can becombined with, for example: corticosteroids; corticosteroid sparingagents such as, but not limited to, azathioprine and methotrexate;intravenous immunoglobulin; immunosuppressive agents such as, but notlimited to, tacrolimus, cyclophosphamide and cyclosporine; rituximab;TNFα inhibitors such as, but not limited to, etanercept and infliximab;growth hormone; growth hormone secretagogues such as, but not limitedto, MK-0677, L-162752, L-163022, NN703 ipamorelin, hexarelin, GPA-748(KP102, GHRP-2), and LY444711 (Eli Lilly); other growth hormone releasestimulators such as, but not limited to, Geref, GHRH (1-44), Somatorelin(GRF 1-44), ThGRF genotropin, L-DOPA, glucagon, and vasopressin; andinsulin-like growth factor.

In certain embodiments wherein Sjögren's syndrome is treated, preventedand/or managed, a compound provided herein can be combined with, forexample: pilocarpine; cevimeline; nonsteroidal anti-inflammatory drugs;arthritis medications; antifungal agents; cyclosporine;hydroxychloroquine; prednisone; azathioprine; and cyclophamide.

Further therapeutic agents that can be combined with a subject compoundcan be found in Goodman and Gilman's “The Pharmacological Basis ofTherapeutics” Tenth Edition edited by Hardman, Limbird and Gilman or thePhysician's Desk Reference, both of which are incorporated herein byreference in their entirety.

The compounds described herein can be used in combination with theagents provided herein or other suitable agents, depending on thecondition being treated. Hence, in some embodiments, the compounds asprovided herein will be co-administered with other agents as describedabove. When used in combination therapy, the compounds described hereincan be administered with the second agent simultaneously or separately.This administration in combination can include simultaneousadministration of the two agents in the same dosage form, simultaneousadministration in separate dosage forms, and separate administration.That is, a compound described herein and any of the agents describedabove can be formulated together in the same dosage form andadministered simultaneously. Alternatively, a compound as providedherein and any of the agents described above can be simultaneouslyadministered, wherein both the agents are present in separateformulations. In another alternative, a compound as provided herein canbe administered just followed by and any of the agents described above,or vice versa. In the separate administration protocol, a compound asprovided herein and any of the agents described above can beadministered a few minutes apart, or a few hours apart, or a few daysapart.

Administration of the compounds as provided herein can be effected byany method that enables delivery of the compounds to the site of action.An effective amount of a compound as provided herein can be administeredin either single or multiple doses by any of the accepted modes ofadministration of agents having similar utilities, including rectal,buccal, intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, as an inhalant, or via an impregnatedor coated device such as a stent, for example, or an artery-insertedcylindrical polymer.

When a compound as provided herein is administered in a pharmaceuticalcomposition that comprises one or more agents, and the agent has ashorter half-life than the compound as provided herein, unit dose formsof the agent and the compound as provided herein can be adjustedaccordingly.

The examples and preparations provided below further illustrate andexemplify the compounds as provided herein and methods of preparing suchcompounds. It is to be understood that the scope of the presentdisclosure is not limited in any way by the scope of the followingexamples and preparations. In the following examples molecules with asingle chiral center, unless otherwise noted, exist as a racemicmixture. Those molecules with two or more chiral centers, unlessotherwise noted, exist as a racemic mixture of diastereomers. Singleenantiomers/diastereomers can be obtained by methods known to thoseskilled in the art.

EXAMPLES Chemical Examples

The chemical entities described herein can be synthesized according toone or more illustrative schemes herein and/or techniques well known inthe art.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure, generally within a temperature range from−10° C. to 200° C. Further, except as otherwise specified, reactiontimes and conditions are intended to be approximate, e.g., taking placeat about atmospheric pressure within a temperature range of about −10°C. to about 110° C. over a period that is, for example, about 1 to about24 hours; reactions left to run overnight in some embodiments canaverage a period of about 16 hours.

The terms “solvent,” “organic solvent,” or “inert solvent” each mean asolvent inert under the conditions of the reaction being described inconjunction therewith including, but not limited to, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, N-methylpyrrolidone (“NMP”), pyridine and the like. Unlessspecified to the contrary, the solvents used in the reactions describedherein are inert organic solvents. Unless specified to the contrary, foreach gram of the limiting reagent, one cc (or mL) of solvent constitutesa volume equivalent.

Isolation and purification of the chemical entities and intermediatesdescribed herein can be effected, if desired, by any suitable separationor purification procedure such as, for example, filtration, extraction,crystallization, column chromatography, thin-layer chromatography orthick-layer chromatography, or a combination of these procedures.Specific illustrations of suitable separation and isolation proceduresare given by reference to the examples hereinbelow. However, otherequivalent separation or isolation procedures can also be used.

When desired, the (R)- and (S)-isomers of the non-limiting exemplarycompounds, if present, can be resolved by methods known to those skilledin the art, for example by formation of diastereoisomeric salts orcomplexes which can be separated, for example, by crystallization; viaformation of diastereoisomeric derivatives which can be separated, forexample, by crystallization, gas-liquid or liquid chromatography;selective reaction of one enantiomer with an enantiomer-specificreagent, for example enzymatic oxidation or reduction, followed byseparation of the modified and unmodified enantiomers; or gas-liquid orliquid chromatography in a chiral environment, for example on a chiralsupport, such as silica with a bound chiral ligand or in the presence ofa chiral solvent. Alternatively, a specific enantiomer can besynthesized by asymmetric synthesis using optically active reagents,substrates, catalysts or solvents, or by converting one enantiomer tothe other by asymmetric transformation.

The compounds described herein can be optionally contacted with apharmaceutically acceptable acid to form the corresponding acid additionsalts. Also, the compounds described herein can be optionally contactedwith a pharmaceutically acceptable base to form the corresponding basicaddition salts.

In some embodiments, disclosed compounds can generally be synthesized byan appropriate combination of generally well known synthetic methods.Techniques useful in synthesizing these chemical entities are bothreadily apparent and accessible to those of skill in the relevant art,based on the instant disclosure. Many of the optionally substitutedstarting compounds and other reactants are commercially available, e.g.,from Aldrich Chemical Company (Milwaukee, Wis.) or can be readilyprepared by those skilled in the art using commonly employed syntheticmethodology.

The discussion below is offered to illustrate certain of the diversemethods available for use in making the disclosed compounds and is notintended to limit the scope of reactions or reaction sequences that canbe used in preparing the compounds provided herein.

General Synthetic Methods

The compounds described, it will be more readily understood by referenceto the following examples, which are included merely for purposes ofillustration of certain aspects and embodiments described herein, andare not intended to limit these aspects and embodiments.

(i) General Method for the Synthesis of Amine Cores

Method A

General conditions for the preparation of(S)-3-(1-aminoethyl)-isoquinolin-1(2H)-ones:

To a stirred mixture of a given o-methylbenzoic acid (A-1) (1.5 mol, 1eq) and DMF (2 mL) in DCM (1275 mL) at RT, oxalyl chloride (1.65 mol,1.1 eq) is added over 5 min and the resulting mixture is stirred at RTfor 2 h. The mixture is then concentrated in vacuo. The residue isdissolved in DCM (150 mL) and the resulting solution (solution A) isused directly in the next step.

To a stirred mixture of a given amine R₂—NH₂ (1.58 mol, 1.05 eq) andtriethylamine (3.15 mol, 2.1 eq) in DCM (1350 mL), the above solution A(150 mL) is added dropwise while the reaction temperature is maintainedbetween 25° C. to 40° C. by an ice-water bath. The resulting mixture isstirred at RT for 2 h and then water (1000 mL) is added. The organiclayer is separated, washed with water (2×1000 mL), dried over Na₂SO₄ andfiltered. The filtrate is concentrated in vacuo. The product issuspended in heptane (1000 mL) and stirred at RT for 30 min. Theprecipitate is collected by filtration, rinsed with heptane (500 mL) andfurther dried in vacuo to afford the amide (A-2).

To a stirred mixture of amide (A-2) (173 mmol, 1 eq) in anhydrous THF(250 mL) at −30° C. under argon, a solution of n-butyllithium in hexanes(432 mol, 2.5 eq) is added dropwise over 30 min while keeping innertemperature between −30° C. and −10° C. The resulting mixture B is thenstirred at −30° C. for 30 min. To a stirred mixture of (S)-tert-butyl1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (260 mmol, 1.5 eq) inanhydrous THF (250 mL) at −30° C. under argon, a solution ofisopropylmagnesium chloride in THF (286 mmol, 1.65 eq) is added dropwiseover 30 min while keeping inner temperature between −30° C. and −10° C.The resulting mixture is stirred at −30° C. for 30 min. This mixture isthen slowly added to above reaction mixture B while keeping the innertemperature between −30° C. and −10° C. The resulting mixture is stirredat −15° C. for 1 h. The reaction mixture is quenched with water (50 mL)and then acidified with conc. HCl at −10° C.-0° C. to adjust the pH to1-3. The mixture is allowed to warm to RT and concentrated in vacuo. Theresidue is dissolved in MeOH (480 mL), and then conc. HCl (240 mL) isadded at RT. The resulting mixture is stirred at reflux for 1 h. Thereaction mixture is cooled to RT and concentrated in vacuo to reduce thevolume to about 450 mL. The residue is extracted with a 2:1 mixture ofheptane and ethyl acetate (2×500 mL). The aqueous layer is basified withconcentrated ammonium hydroxide to adjust the pH to 9-10 while keepingthe inner temperature between −10° C. and 0° C. The mixture is thenextracted with DCM (3×300 mL), washed with brine, dried over MgSO₄ andfiltered. The filtrate is concentrated in vacuo and the residue isdissolved in MeOH (1200 mL) at RT. To this solution, D-(−)-tartaric acid(21 g, 140 mmol, 0.8 eq) is added in one portion at RT. After stirringat RT for 30 min, a solid precipitate forms and the mixture is slurriedat RT for 10 h. The solid is collected by filtration and rinsed withMeOH (50 mL×3). The collected solid is suspended in water (500 mL) andthen neutralized with concentrated ammonium hydroxide solution at RT toadjust the pH to 9-10. The mixture is extracted with DCM (200 mL×3). Thecombined organic layers are washed with brine, dried over MgSO₄ andfiltered. The filtrate is concentrated in vacuo to afford(S)-3-(1-aminoethyl)-isoquinolin-1(2H)-ones (A-3).

Method A′

General conditions for the preparation of(S)-3-(1-aminoethyl)-isoquinolin-1(2H)-ones:

In one embodiment, an amino compound (A-3′) may be prepared followingMethod A′, wherein the intermediate (A-1′) may be prepared followingprocedures known in the art or the procedure as described in Method A.In one embodiment, intermediate (A-2′) may be prepared from intermediate(A-1′) by contacting intermediate (A-1′) with a base (e.g., ^(n)BuLi)followed by (S)-benzyl(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate. In one embodiment,the amino compound (A-3′) may be prepared from intermediate (A-2′) bycyclizing intermediate (A-2′) in the presence of an acid. In oneembodiment, the acid is H₂SO₄. In another embodiment, the acid is HCl.In one embodiment, the amount of the acid is about 1 to 20 equivalentsrelative to the amount of the intermediate (A-2′). In one embodiment,the acid is about 5 equivalents of H₂SO₄. In one embodiment, thecyclization occurs at about room temperature to 65° C. In oneembodiment, the cyclization occurs at about 65° C. for about 1 to 5hours.

In one embodiment, the cyclization provides the amino compound (A-3′)with a ratio of (S)-enantiomer to (R)-enantiomer of about 1:1 to 20:1.In one embodiment, the cyclization provides the amino compound (A-3′)with a ratio of (S)-enantiomer to (R)-enantiomer of about 1:1 to 10:1.In one embodiment, the cyclization provides the amino compound (A-3′)with a ratio of (S)-enantiomer to (R)-enantiomer of about 1:1 to 4:1. Itis to be understood that the methods provided herein are also suitablefor the preparation of (R)-enantiomer of the amino compound (A-3′) when(R)-benzyl (1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate is usedin place of (S)-benzyl(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate.

Method B

General conditions for the preparation of(S)-3-(1-aminoethyl)-isoquinolin-1(2H)-ones:

To 2-chloro-6-methylbenzoic acid (B-1) (8.00 g, 46.9 mmol) in a dryround bottom flask under N₂ is added 50 mL of dry THF. The resultingmixture is cooled to −25° C. Then, n-hexyllithium (88 mL, 202 mmol) (2.3M in hexanes) is added, and the reaction is stirred at −20° C. for about20 min.

To compound (B-2) (14.16 g, 61.0 mmol) in a second dry round bottomflask under N₂ is added 70 mL of dry THF. The mixture is cooled to about−10° C. To the cold mixture is slowly added isopropyl magnesium chloride(63.3 ml, 2 M, 127 mmol). The resulting mixture is then stirred at −10°C. for about 20 min. Then, this mixture is slowly cannulated drop wiseinto the flask containing the (B-1) reaction while maintaining thetemperature at −20° C. After addition is complete, the reaction isslowly warmed to RT and stirred at RT for about 1.6 hours. The reactionmixture is then cooled to −10° C. and quickly cannulated to anotherflask containing 15 mL of ethyl acetate and 10 mL of isobutyric acid at−10° C. under N₂. After stirring for about 5 minutes, 10 mL of water israpidly added. The cooling bath is removed, and the reaction mixture isstirred for 10 minutes at RT. The mixture is transferred to a separationfunnel, and water (200 mL) is added. The water layer is extracted withEtOAc (3×400 mL). The aqueous layer is then acidified with HCl (2M) topH 3, and is extracted with EtOAc (3×500 mL), dried over sodium sulfateand concentrated in vacuo. The resulting material is purified by silicagel column chromatography using 0-10% MeOH in DCM to afford benzoic acid(B-3).

A mixture of benzoic acid (B-3) (5.00 g, 14.63 mmol) in acetic anhydride(10 mL) is stirred in a round bottom flask at 70° C. for about 2.5hours. Then, the remaining acetic anhydride is removed in vacuo. Theresidue is purified using silica gel column chromatography usingEtOAc/hexanes to afford lactone (B-4).

To a mixture of R₂—NH₂ (197 mg, 1.54 mmol) in 2 mL of DCM is added AlMe₃(0.772 ml, 1.54 mmol). The mixture is stirred for about 15 min. Then, asolution of lactone (B-4) (100 mg, 0.309 mmol) in 2 mL of DCM is added,and the reaction is stirred at RT for about 3 hours. The reactionmixture is then quenched with addition of 10 mL of Rochelle's salt andstirring for about 2 hours. The mixture is diluted with DCM, washed withbrine, dried with Na₂SO₄ and concentrated in vacuo to afford the amide(B-5) which is carried directly to the next reaction.

To the amide (B-5) in 5 mL of isopropanol is added 3 mL of concentratedHCl. The reaction is heated at 65° C. for about 3 hours. After coolingto RT, the mixture is concentrated in vacuo. The solid is suspended in15 mL of DCM, followed by the addition of 10 mL of sat. NaHCO₃. Thismixture is then stirred at RT for about 30 min, then 50 mL of DCM isadded. The layers are separated and the organic layer is dried withNa₂SO₄ and concentrated in vacuo to afford isoquinolinone (B-6).

The following isoquinolinone compounds (B-6) given in Table 3 were madein analogous fashion to Method B using the following R₂—NH₂ reagents.

Method B′

General conditions for the preparation of(S)-3-(1-aminoethyl)-isoquinolin-1(2H)-ones:

In some embodiments, isoquinolinone (B-6) may be prepared by followingthe procedures exemplified in Method B′. In one embodiment, intermediate(B-2′) is prepared by contacting intermediate (B-2) with TFA followed byCF₃COOEt. In one embodiment, benzoic acid (B-3′) is prepared bycontacting o-methyl-benzoic acid (B-1) with a base (e.g., nHexLi),followed by intermediate (B-2′), and followed by purification by silicaplug or crystallization. In one embodiment, lactone (B-4′) is preparedby contacting benzoic acid (B-3′) with Ac₂O under conditions suitablefor cyclization. In one embodiment, amide (B-5′) is prepared bycontacting lactone (B-4′) with corresponding amine or aniline in thepresence of AlMe₃. In one embodiment, isoquinolinone (B-6) is preparedby contacting amide (B-5′) with an acid under conditions suitable forcyclization and deprotection. In one embodiment, the acid is HCl.

In one embodiment, the cyclization provides the amino compound (B-6)with a ratio of (S)-enantiomer to (R)-enantiomer of about 1:1 to 20:1.In one embodiment, the cyclization provides the amino compound (B-6)with a ratio of (S)-enantiomer to (R)-enantiomer of about 1:1 to 10:1.In one embodiment, the cyclization provides the amino compound (B-6)with a ratio of (S)-enantiomer to (R)-enantiomer of about 1:1 to 4:1. Itis to be understood that the methods provided herein are also suitablefor the preparation of (R)-enantiomer of the amino compound (B-6) when(R)-enantiomer of intermediate (B-2) is used in place of (S)-enantiomerof (B-2).

TABLE 3 Compounds (B-6) R₂—NH₂ Compound (B-6) ESI-MS m/z: [M + H]⁺

299.10

335  

324.12

313.10

329.09

383.13

300.09

290.06

Method C

To a suspension of 2-amino-6-methylbenzoic acid (C-1) (20.0 g, 132.0mmol, 1.0 eq) in H₂O (55 mL) at 0-5° C., conc. HCl (36.5%, 64 mL, 749mmol, 5.7 eq) is added slowly. After stirring for 15 min, the mixture isadded dropwise to a solution of sodium nitrite (12.02 g, 174.0 mmol,1.32 eq) in H₂O (36 mL) at 0-5° C., and the resulting mixture is stirredfor 1 h. The resulting solution is then added to a solution of KI (60.5g, 364.5 mmol, 2.76 eq) in H2O (150 mL) at 0-5° C. The reaction mixtureis allowed to warm to RT and stirred at RT overnight. The mixture isextracted with ethyl acetate (3×100 mL). The combined organic layers arewashed with water (2×100 mL), dried over anhydrous Na₂SO₄ and filtered.The filtrate is concentrated in vacuo and the residue is purified byflash column chromatography on silica gel (0-20% ethyl acetate-petroether) to afford the product, 2-iodo-6-methylbenzoic acid (C-2).

To a stirred mixture of 2-iodo-6-methylbenzoic acid (C-2) (305.3 mmol,1.0 eq) and DMF (0.3 mL) in DCM (350 mL) at RT, oxalyl chloride (466.4mmol, 1.5 eq) is added dropwise. The resulting mixture is stirred at RTfor 3 h and then concentrated in vacuo. The residue is dissolved in DCM(50 mL) and the resulting solution (solution A) is used directly in thenext step. To a stirred mixture of R³-substituted aniline (335.7 mmol,1.1 eq) and triethylamine (915.0 mmol, 3.0 eq) in DCM (350 mL), solutionA (150 mL) is added dropwise while the reaction temperature iscontrolled below 30° C. by an ice-water bath. The reaction mixture isstirred at RT for 1 h and then quenched with water (200 mL). The organiclayer is separated, washed with water (2×200 mL), dried over anhydrousNa₂SO₄ and filtered. The filtrate is concentrated in vacuo. The productis rinsed with isopropyl ether and dried in vacuo to afford the productamide (C-3).

A mixture of amide (C-3) (18.0 mmol, 1.0 eq), methyl2,2-difluoro-2-(fluorosulfonyl)acetate (72.9 mmol, 4.0 eq) and CuI (3.63mmol, 0.2 eq) in DMF (130 mL) is stirred at 70° C. under an argonatmosphere overnight. The mixture is allowed to cool to RT and thenconcentrated in vacuo to remove the solvent. The resulting residue ispartitioned between ethyl acetate (60 mL) and water (60 mL), and theaqueous layer is extracted with ethyl acetate (2×60 mL). The combinedorganic layers are washed with water (2×60 mL), dried over anhydrousNa₂SO₄ and filtered. The filtrate is concentrated in vacuo and theresidue is purified by flash column chromatography on silica gel toafford the product, trifluoromethyl amide (C-4).

To a stirred mixture of amide (C-4) (10.1 mmol, 1.0 eq) in anhydrous THF(25 mL) at −40° C. under an argon atmosphere, a solution ofn-butyllithium in THF (2.5M, 25.3 mmol, 2.5 eq) is added dropwise (over15 min) and the inner temperature is controlled between −30° C. and −20°C. during the addition. The resulting mixture is stirred at −30° C. foran additional 1 h. To a stirred mixture of (S)-tert-butyl1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (11.1 mmol, 1.1 eq)in anhydrous THF (20 mL) at −30° C. under an argon atmosphere, asolution of isopropylmagnesium chloride in THF (12.6 mmol, 1.25 eq) isadded dropwise (over 15 min) and the inner temperature is controlledbelow −20° C. during the addition. The resulting mixture is stirred at−15° C. for 1 h. This solution is then slowly added to the abovereaction mixture at −30° C. (over 10 min), and the resulting mixture isstirred at −30° C. for an additional 30 min. The reaction mixture isquenched with water (50 mL) and then acidified with conc. HCl at −5° C.to adjust the pH to 5. The mixture is allowed to warm to RT andconcentrated in vacuo. The residue is dissolved in MeOH (10 mL), andthen conc. HCl (10 mL) is added quickly at RT. The resulting mixture isstirred at reflux for 2 h, cooled to RT and then concentrated in vacuo.The residue is suspended in water (15 mL), basified with concentratedammonium hydroxide to adjust the pH to 9-10 while keeping the innertemperature below 5° C. and then extracted with DCM (3×15 mL). Thecombined organic layers are washed with brine, dried over MgSO₄ andfiltered. The filtrate is concentrated in vacuo and the residue isdissolved in MeOH (70 mL).

To this solution, D-(−)-tartaric acid (8.1 mmol, 0.8 eq) is added in oneportion at RT. After stirring at RT for 30 min, a solid precipitates andthe mixture is slurried at RT for 10 h. The precipitate is collected byfiltration and rinsed with MeOH (3×4.0 mL). The collected solid issuspended in water (30 mL) and then neutralized with concentratedammonium hydroxide solution at RT to adjust the pH to 9-10. The mixtureis extracted with DCM (3×15 mL). The combined organic layers are washedwith brine, dried over anhydrous MgSO₄ and filtered. The filtrate isconcentrated in vacuo to afford the product,(S)-3-(1-aminoethyl)-8-(trifluoromethyl)isoquinolin-1(2H)-one (C-5).

(ii) General Method for Synthesis of(S)-2-(1-aminoethyl)-quinazolin-4(3H)-one amine core

Method D

General conditions for the preparation of(S)-2-(1-aminoethyl)-quinazolin-4(3H)-ones:

To a stirred mixture of nitrobenzoic acid (D-1) (1.0 mol, 1.0 eq) andDMF (2.0 mL) in toluene (800 mL), thionyl chloride (1.0 mol, 4.0 eq) isadded dropwise (over 15 min) and the resulting mixture is stirred atreflux for 1.5 h. The mixture is allowed to cool to RT and thenconcentrated in vacuo. The residue is dissolved in DCM (100 mL) to formsolution A, which is used directly in the next step.

To a stirred mixture of a given amine R₂—NH₂ (1.1 mol, 1.1 eq) andtriethylamine (2.0 mol, 2.0 eq) in DCM (700 mL), solution A is addeddropwise while the reaction temperature is maintained below 10° C. Theresulting mixture is allowed to warm to RT and stirred at RT overnight.The reaction mixture is diluted with ice-water (1.0 L) and stirred for15 min. The solid is collected by filtration, rinsed with isopropylether (3×100 mL) and petroleum ether (3×100 mL), and then dried in vacuoto afford amide (D-2).

To a mixture of amide (D-2) (20.0 mmol, 1.0 eq) and DMF (catalyticamount) in toluene (60 mL) at RT, thionyl chloride (164 mmol, 8.2 eq) isadded dropwise (over 5 min). The resulting mixture is stirred at refluxfor 2 h. The mixture is allowed to cool to RT and concentrated in vacuo.The residue is dissolved in DCM (10 mL) to form solution B, which isused directly in the next step.

To a mixture of N-(tert-butoxycarbonyl)-L-alanine (16.0 mmol, 0.8 eq)and N,N-diisopropylethylamine (31.0 mol, 1.5 eq) in DCM (20 mL), abovesolution B is added dropwise while the reaction temperature ismaintained at 10° C. The resulting mixture is stirred for an additional1 h at this temperature and then stirred at RT overnight. The reactionmixture is quenched with ice-water (100 mL). The organic layer isseparated and the aqueous layer is extracted with DCM (2×80 mL). Thecombined organic layers are washed with brine, dried over Na₂SO₄ andfiltered. The filtrate is concentrated in vacuo and the residue isslurried in isopropyl ether (100 mL) for 15 min. The precipitate iscollected by filtration and then dried in vacuo to afford product (D-3).

To a suspension of zinc dust (110 mmol, 10.0 eq) in glacial acetic acid(40 mL) at 15° C., a mixture of (D-3) (11.0 mmol, 1.0 eq) in glacialacetic acid (40 mL) is added and the resulting mixture is stirred at RTfor 4 h. The mixture is poured into ice-water (200 mL) and neutralizedwith saturated aqueous NaHCO₃ solution to adjust the pH value to 8. Theresulting mixture is extracted with DCM (3×150 mL). The combined organiclayers are washed with brine, dried over Na₂SO₄ and filtered. Thefiltrate is concentrated in vacuo and the residue is purified by flashchromatography on silica gel eluting with 7% ethyl acetate/petroleumether to afford product (D-4).

A mixture of (D-4) (0.5 mmol, 1.0 eq) in HCl methanol solution (2 N, 20mL) is stirred at RT for 2 h. The mixture is concentrated in vacuo. Theresidue is diluted with water (30 mL) and then neutralized withsaturated aqueous NaHCO₃ to adjust the pH value to 8 while thetemperature is maintained below 5° C. The resulting mixture is extractedwith DCM (3×30 mL). The combined organic layers are washed with brine,dried over Na₂SO₄ and filtered. The filtrate is concentrated in vacuoand the residue is slurried in petroleum ether (10 mL). The solid iscollected by filtration and dried in vacuo to afford product (D-5).

(iii) General Method for the Synthesis of Cl-Wd

Method E

General conditions for the preparation of2-amino-4-chloropyrimidine-5-carbonitrile:

To a solution of 2,4-dichloropyrimidine-5-carbonitrile (E-1) (2.0 g,11.5 mmol) in 1,4-dioxane (20 mL) at 0° C., ammonium hydroxide (28-30%,4.4 mL, 34.5 mmol) is added dropwise, and the resulting mixture isstirred while warming from 0° C. to RT for 2 h. Then, the mixture ispartitioned between ethyl acetate (200 mL) and water (50 mL). Theorganic layer is washed with brine, dried over Na₂SO₄ and filtered. Thefiltrate is mixed with silica gel and then concentrated in vacuo. Theresidue is purified by silica gel chromatography eluting with 0-100%ethyl acetate/hexanes to afford the product (E-2) (917 mg) and a mixtureof (E-2) and (E-3). Additional (E-3) can be obtained from this mixtureby a second column chromatographic purification.

Method E′

In one embodiment, 2-amino-4-chloropyrimidine-5-carbonitrile (E-2) maybe prepared following procedures exemplified in Method E′. In oneembodiment, compound (E-2) may be prepared by contacting2,4-dichloropyrimidine-5-carbonitrile (E-1) with ammonium hydroxide in asolvent of THF. In one embodiment, the reaction temperature is about−50° C. In one embodiment, the reaction provides a mixture of compounds(E-2) and (E-3) with a ratio of (E-2) to (E-3) of about 4:1. In oneembodiment, compound (E-2) is further purified by crystallization fromTHF.

Method F

General conditions for the preparation of4-chloro-5-(trifluoromethyl)pyrimidin-2-amine:

To stirred neat 2,4-dichloro-5-(trifluoromethyl)pyrimidine (F-1) (5.0 g,23.04 mmol) under argon, ammonia in methanol (7N solution, 15 mL) isadded dropwise and the resulting mixture is stirred at RT for 2 h. Thereaction mixture is quenched with water and then extracted with ethylacetate (200 mL×2). The combined organic layers are washed with brine,dried over Na₂SO₄ and filtered. The filtrate is concentrated in vacuoand the residue is purified by flash chromatography on silica geleluting with 0-20% ethyl acetate/hexanes to afford the product,4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (F-2) (1.03 g, 22.6%yield). The other regio-isomer,2-chloro-5-(trifluoromethyl)pyrimidin-4-amine (F-3), can also beisolated.

(iv) General Conditions for Attachment of W_(d) Substituents

Method G

(S)-3-(1-Aminoethyl)-isoquinolin-1(2H)-one (A-3) (115 mmol, 1.0 eq),Cl-Wd or Wd-OTs (173 mmol, 1.5 eq) and triethylamine (344 mmol, 3.0 eq)are dissolved in n-BuOH (350 mL) and the mixture is stirred at refluxfor 16 h. The reaction mixture is cooled to RT and concentrated invacuo. The residue is suspended in a mixture of H₂O (200 mL) and ethylacetate (100 mL) and stirred at RT for 30 min. The solid is thencollected by filtration, rinsed with ethyl acetate (25 mL) and dried invacuo to afford the product (G-1). The reaction can occur under otherconditions known in the art that are suitable for S_(N)Ar displacementreaction. In one embodiment, the reaction solvent is NMP.

(v) Methods for Synthesis of Substituted quinazolin-4(3H)-one Cores

Method H

A mixture of compound 8 (0.12 mmol, 1.0 equiv.),2-(R¹)-5-(tributylstannyl)thiazole (H-2) (0.24 mmol, 2.0 equiv.), andPd(0) catalyst (0.024 mmol, 0.2 equiv.) in 1 ml degassed DMF is heatedfor 3 h. before partitioning between EtOAc and water. The organic layeris collected, the aqueous layer is extracted with EtOAc, and thecombined EtOAc layers are washed with brine. The solvent is removed andthe residue purified on silica gel to provide (H-3).

Method I

A mixture of compound 8 (0.4 mmol, 1.0 equiv.), (1-R¹)Ethynyltributylstannane (I-1) (0.8 mmol, 2.0 equiv.), and Pd(0) catalyst (0.08mmol, 0.2 equiv.) in 3 ml degassed DMF is heated for 5 h. beforepartitioning between EtOAc and water. The organic layer is collected,the aqueous layer is extracted with EtOAc, and the combined EtOAc layersare washed with brine. The solvent is removed and the residue ispurified on silica gel to provide (I-2).

Method J

A mixture of compound 8 (0.17 mmol, 1.0 equiv.), boronic acid orboronate (J-1) (0.34 mmol, 2.0 equiv.), base (0.85 mol, 5 equiv.) andPd(0) catalyst (0.034 mmol, 0.2 equiv.) in 1.5 ml degassed 4:1dioxane-water is heated for 1 h. before partitioning between EtOAc andwater. The organic layer is collected, the aqueous layer is extractedwith EtOAc, and the combined EtOAc layers are washed with brine. Thesolvent is removed and the residue is purified on silica gel to provide(J-2).

A compound of Formula (I) (e.g., H-3, I-2, and J-2) may contain one ormore chiral center. Conventional techniques for thepreparation/isolation of individual enantiomers include synthesis from asuitable optically pure precursor, asymmetric synthesis from achiralstarting materials, or resolution of an enantiomeric mixture, forexample, by chiral chromatography, recrystallization, resolution,diastereomeric salt formation, or derivatization into diastereomericadducts followed by separation. In one embodiment, the enantiopurity ofa compound of Formula (I) may be improved by contacting the compound ofFormula (I) with a suitable solvent or mixture thereof, followed byfiltration. In one embodiment, the solvent is a mixture of water anddichloromethane. In another embodiment, the solvent is a mixture ofdichloromethane and methanol.

(vi) Methods for Synthesis of N-methyl pyridinone boronic esters

Method K

In one embodiment, the N-methyl pyridinone boronic ester (K-3) may beprepared following procedures exemplified in Method K. In oneembodiment, pyridyl boronic ester (K-2) may be prepared by contactingpyridyl boronic acid (K-1) with pinacol under conditions suitable forthe formation of boronic esters. In one embodiment, the N-methylpyridinone boronic ester (K-3) may be prepared by contacting pyridylboronic ester (K-2) with MeI under conditions suitable forO-methyl-to-N-methyl shifting.

Example 1

Amine 1 was prepared from commercially available2-chloro-6-methylbenzoic acid according to Method A. Amine 1 was thenconverted to compound 2 according to the following procedure:

To a mixture of(S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one 1 (1.41 g,4.72 mmol) and (2-methoxypyrimidin-5-yl)boronic acid (1.09 g, 7.08 mmol)in anhydrous DMA (20 mL) in a sealed tube, PdCl₂(dppf) (309 mg, 0.38mmol) and aqueous Na₂CO₃ solution (1 M, 14.2 mL, 14.2 mmol) were addedand the resulting mixture was stirred at 120° C. for 16 h. The reactionmixture was allowed to cool to RT, quenched with water, and thenextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo and the residue was slurried in ether for 10 min.The solid was collected by filtration, rinsed with ether and dried invacuo to afford a first amount of product 2. The filtrate wasconcentrated in vacuo and the residue was further purified by ISCOcolumn chromatography using a silica gel cartridge and eluting with 0-8%MeOH-DCM to afford a second amount of product 2.

Compound 2 was coupled to 2,4-dichloro-5-iodopyrimidine to affordcompound 3 according to Method G. Compound 3 was then converted tocompound 5 according to the following procedures:

To a solution of(S)-3-(1-((2-chloro-5-iodopyrimidin-4-yl)amino)ethyl)-8-(2-methoxypyrimidin-5-yl)-2-phenylisoquinolin-1(2H)-one3 (800 mg, 1.31 mmol) in anhydrous 1,4-dioxane (4 mL) in a sealed tube,ammonium hydroxide (7 mL) was added and the resulting mixture wasstirred at 110° C. for 20 h. The mixture was allowed to cool to RT,quenched with water and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over Na₂SO₄ and filtered.The filtrate was concentrated in vacuo and the residue was purified byISCO column chromatography using a silica gel cartridge and eluting with0-8% MeOH-DCM to afford the product,(S)-3-(1-((2-amino-5-iodopyrimidin-4-yl)amino)ethyl)-8-(2-methoxypyrimidin-5-yl)-2-phenylisoquinolin-1(2H)-one 4.

To a solution of(S)-3-(1-((2-amino-5-iodopyrimidin-4-yl)amino)ethyl)-8-(2-methoxypyrimidin-5-yl)-2-phenylisoquinolin-1(2H)-one4 (352 mg, 0.60 mmol) in anhydrous acetonitrile (20 mL) in a sealedtube, sodium cyanide (292 mg, 5.95 mmol), tetrakis(triphenylphosphine)palladium(0) (344 mg, 0.30 mmol), and copper iodide (80 mg, 0.42 mmol)were added, and the resulting mixture was stirred at 80° C. for 16 h.The mixture was allowed to cool to RT, quenched with water and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over Na₂SO₄ and filtered. The filtrate was concentrated in vacuoand the residue was purified by ISCO column chromatography using asilica gel cartridge and eluting with 0-8.5% MeOH-DCM to afford theproduct,(S)-2-chloro-4-((1-(8-(2-methoxypyrimidin-5-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carbonitrile5. ESI-MS m/z: 491.2 [M+H]⁺.

Example 2

Compound 1 was coupled to 2,4-dichloro-5-iodopyrimidine to affordcompound 6 according to Method G. Compound 6 was then converted to 7 inanalogous fashion to compound 4 in Example 1.

Compound 7 was then converted to 9 in 2 steps according to the followingprocedures:

To a solution of(S)-3-(1-((2-amino-5-iodopyrimidin-4-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one7 (700 mg, 1.35 mmol) in DMF (40 mL), cyanocopper (243 mg, 2.7 mmol),tetrakis(triphenylphosphine) palladium(0) (779 mg, 0.68 mmol), andcopper iodide (180 mg, 0.95 mmol) were added and the resulting mixturewas stirred at 80° C. for 16 h. The mixture was allowed to cool to RT,quenched with water and extracted with ethyl acetate (2×50 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄ andfiltered. The filtrate was concentrated in vacuo and the residue waspurified by flash column chromatography on silica gel eluting with 0-10%MeOH-DCM to afford the product,(S)-2-amino-4-((1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carbonitrile8.

To a mixture of(S)-2-amino-4-((1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carbonitrile8 (50 mg, 0.12 mmol) and (5-methoxypyridin-3-yl)boronic acid (37 mg,0.24 mmol) in anhydrous 1,4-dioxane (4 mL), PdCl₂(dppf) (9.8 mg, 0.012mmol) and aqueous Na₂CO₃ solution (1 M, 0.6 mL, 0.6 mmol) were added andthe resulting mixture was stirred at 120° C. for 3 h. The reactionmixture was allowed to cool to RT, quenched with water, and thenextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with brine, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by flash columnchromatography on silica gel eluting with 0-10% MeOH-DCM to afford theproduct,(S)-2-amino-4-((1-(8-(5-methoxypyridin-3-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carbonitrile9. ESI-MS m/z: 490.2 [M+H]⁺. Compound2-amino-4-((S)-1-(8-(5-methoxypyridin-3-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethylamino)pyrimidine-5-carboxamide10 was also formed in the above reaction and it was isolated by columnchromatography. ESI-MS m/z: 508.2 [M+H]^(f).

Example 3

Compound 8 was prepared from compound 1 and (E-2) using Method G. ESI-MSm/z: 417.2 [M+H]⁺.

Example 4

Compound 11 was prepared from compound 5 according to the followingprocedure:

To a solution of(S)-2-amino-4-((1-(8-(2-methoxypyrimidin-5-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carbonitrile5 (34 mg, 0.070 mmol) in anhydrous toluene (4 mL) under argon,acetaldoxime (13 μL, 0.21 mmol), palladium(II) acetate (5 mg, 0.01 mmol)and triphenyl phosphine (5 mg, 0.017 mmol) were added and the resultingmixture was stirred at 80° C. for 3 h. The mixture was allowed to coolto RT and partitioned between water and ethyl acetate. The organic layerwas washed with brine, dried with Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by ISCO columnchromatography (silica gel cartridge, 0-10% MeOH/DCM) to afford theproduct,(S)-2-amino-4-((1-(8-(2-methoxypyrimidin-5-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carboxamide11. ESI-MS m/z: 509.2 [M+H]⁺.

Example 5

Compound 12 was prepared by coupling compound 2 with4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (F-2), prepared by MethodF, according to Method G. ESI-MS m/z: 534.2 [M+H]⁺.

Example 6

Compound 13 was prepared from compound 9 according to the followingprocedure:

To a stirred mixture of(S)-2-amino-4-((1-(8-(5-methoxypyridin-3-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carbonitrile9 (15 mg, 0.031 mmol) in DCM (5 mL) at −78° C. under argon, PBr₃ (77 mg,0.31 mmol) was added and the resulting mixture was stirred from −78° C.to RT overnight. The reaction mixture was poured into ice-water (10 mL)and then neutralized with saturated aqueous NaHCO₃ to adjust the pHvalue to 8-9. The mixture was extracted with a mixture of methanol inDCM (5%, 5×10 mL). The organic layer was dried over Na₂SO₄ and filtered.The filtrate was concentrated in vacuo and the residue was purified byflash column chromatography on silica gel eluting with 1-3% MeOH/DCM toafford2-amino-4-((S)-1-(8-(5-hydroxypyridin-3-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethylamino)pyrimidine-5-carbonitrile13. ESI-MS m/z: 476.0 [M+H]⁺.

Example 7

Amine 14 was prepared from commercially available 2,6-dimethylbenzoicacid according to Method A. Compound 14 was coupled to2-amino-4-chloropyrimidine-5-carbonitrile (E-2) according to Method G toafford compound 15. ESI-MS m/z: 415.2 [M+H]⁺.

Example 8

Compound 16 was prepared from compound 14 by coupling with4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (F-2) according to MethodG. ESI-MS m/z: 458.0 [M+H]⁺.

Example 9

Amine 17 was prepared from commercially available2-chloro-6-methylbenzoic acid according to Method A. Compound 17 wascoupled to 2-amino-4-chloropyrimidine-5-carbonitrile (E-2) according toMethod G to afford compound 18. ESI-MS m/z: 435.0 [M+H]⁺.

Example 10

Compound 19 was prepared from amine 17 in analogous fashion to compound2 in Example 1. Compound 19 was coupled to2-amino-4-chloropyrimidine-5-carbonitrile (E-2) according to Method G toafford compound 20. ESI-MS m/z: 493.2 [M+H]⁺.

Example 11

Compound 21 was prepared in analogous fashion to compound 2 inExample 1. Compound 22 was prepared by coupling compound 21 with2-amino-4-chloropyrimidine-5-carbonitrile (E-2) according to Method G.ESI-MS m/z: 509.2 [M+H]⁺.

Example 12

Compound 23 was prepared from compound 28 in analogous fashion tocompound 2 in Example 1. ESI-MS m/z: 528.2 [M+H]⁺.

The following compounds were also prepared from compound 18 by Suzukicoupling with various commercially available or self-preparedheterocyclic aryl boronic acid/boronates in analogous fashion tocompound 23 in Example 12.

Example Compound Boronic acid/pinacol ester ESI-MS m/z 13

492.2 [M + H]⁺ 24 14

517.2 [M + H]⁺ 25 15

492.2 [M + H]⁺ 26 16

508.2 [M + H]⁺ 27 17

508.2 [M + H]⁺ 28

Example 18

Compound 29 was prepared from amine 17 in analogous fashion to compound2 in Example 1 except that 4-(tributylstannyl)pyridazine was used inplace of (2-methoxypyrimidin-5-yl)boronic acid. Compound 29 was coupledto 2-amino-4-chloropyrimidine-5-carbonitrile (E-2) according to Method Gto afford compound 30. ESI-MS m/z: 479.2 [M+H]⁺.

Example 19

Compound 21 was prepared from amine 17 in analogous fashion to compound2 in Example 1. Compound 21 was coupled to4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (F-2) according to MethodG to afford compound 31. ESI-MS m/z: 552.0 [M+H]⁺.

The following compounds were prepared from compound 1 in two steps bySuzuki coupling with an aryl or heteroaryl boronic acid/pinacol ester(commercially purchased or self-prepared) in analogous fashion tocompound 2 in Example 1, followed by coupling to2-amino-4-chloropyrimidine-5-carbonitrile (E-2) (prepared by Method E)according to Method G.

Example Compound Boronic acid/pinacol ester ESI-MS m/z 20

493.0 [M + H]⁺ 32 21

477.0 [M + H]⁺ 33 22

493.0 [M + H]⁺ 34 23

490.0 [M + H]⁺ 35 24

489.0 [M + H]⁺ 36 25

477.0 [M + H]⁺ 37 26

489.2 [M + H]⁺ 38 27

473.0 [M + H]⁺ 39 28

502.0 [M + H]⁺ 40 29

474.0 [M + H]⁺ 41 30

502.0 [M + H]⁺ 42 31

484.0 [M + H]⁺ 43 32

484.0 [M + H]⁺ 44 33

538.0 [M + H]⁺ 45 34

473.2 [M + H]⁺ 46

The following compounds were prepared from compound 8 (Example 3) bySuzuki coupling with various heterocyclic aryl/heteroaryl boronic acidor pinacol ester according to the coupling conditions in Example 2:

Example Compound Boronic Acid ESI-MS m/z 35

499.2 [M + H]⁺ 47 36

474.2 [M + H]⁺ 48 37

490.2 [M + H]⁺ 49 38

510.22 [M + H]⁺ 50 39

474.2 [M + H]⁺ 51 40

528.0 [M + H]⁺ 52 41

518.0 [M + H]⁺ 53

Example 42

Compound 55 was prepared from compound 1 in two steps in an analogousfashion to compound 30 in Example 18. ESI-MS m/z: 475.2 [M+H]⁺.

Example 43

Compound 57 was prepared from compound 1 in two steps in an analogousfashion to compound 30 in Example 18. ESI-MS m/z: 461.2 [M+H]⁺.

Example 44

Compound 58 was prepared from 2-chloro-6-nitrobenzoic acid according toMethod D. Compound 58 was coupled to (E-2) according to Method G toafford compound 59. Compound 59 was converted to compound 60 by Suzukicoupling with (2-methoxypyrimidin-5-yl)boronic acid in analogous fashionto compound 2 in Example 1. ESI-MS m/z: 492.2 [M+H]⁺.

The following compounds were also prepared from compound 59 by Suzukicoupling with heteroaryl boronic acid or pinacol ester in analogousfashion to compound 60 in Example 44.

Example Compound Boronic Acid ESI-MS m/z 45

464.2 [M + H]⁺ 61 46

475.2 [M + H]⁺ 62

Example 47

Compound 63 was prepared from 59 according to the following procedure:

To a mixture of(S)-2-amino-4-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile59 (50 mg, 0.12 mmol) and2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (40mg, 0.18 mmol) in a 4:1 mixture of 1,4-dioxane and water (4 mL) in asealed tube, Na₂CO₃ (38 mg, 0.36 mmol), RuPhos (28 mg, 0.06 mmol) andPd(OAc)₂ (6.8 mg, 0.03 mmol) were added. The mixture was degassed andback-filled with argon (three cycles) and then stirred at 120° C. for 1h. The reaction mixture was allowed to cool to RT, and then partitionedbetween ethyl acetate and water. The organic layer was washed withbrine, dried over Na₂SO₄ and filtered. The filtrate was concentrated invacuo and the residue was purified by ISCO column chromatography (silicagel cartridge, 0-10% MeOH-DCM) to afford the product,(S)-2-amino-4-((1-(5-(2-methylpyrimidin-5-yl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile63. ESI-MS m/z: 476.2 [M+H]⁺.

Example 48

Compound 64 was prepared from amine 58 in analogous fashion to compound2 in Example 1. Compound 64 was coupled to (E-2) according to Method Gto afford compound 65. ESI-MS m/z: 491.2 [M+H]⁺.

Example 49

Compound 66 was prepared from 59 according to the following procedure:

A mixture of(S)-2-amino-4-(1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile59 (50 mg, 0.12 mmol), 4-(tributylstannyl)pyridazine (89 mg, 0.24 mmol)and PdCl₂(dppf) (9.7 mg, 0.012 mmol) in 1,4-dioxane (5 mL) was stirredat reflux under argon for 16 h. The mixture was allowed to cool to RT,poured into water (20 mL) and extracted with ethyl acetate (2×15 mL).The combined organic layers were washed with brine, dried over Na₂SO₄and filtered. The filtrate was concentrated in vacuo and the residue waspurified by flash column chromatography on silica gel eluting with 3%MeOH-DCM to afford the product,(S)-2-amino-4-((1-(4-oxo-3-phenyl-5-(pyridazin-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile66. ESI-MS m/z: 462.2 [M+H]⁺.

Example 50

Compound 68 was prepared from compound 8 in analogous fashion to MethodH. ESI-MS m/z: 480.3 [M+H]⁺.

Example 51

Compound 70 was prepared from compound 8 in analogous fashion to MethodH. ESI-MS m/z: 496.3 [M+H]⁺.

Example 52

Compound 72 was prepared from compound 8 in analogous fashion to MethodI. ESI-MS m/z: 407.23 [M+H]⁺.

Example 53

Compound 74 was prepared from compound 8 in analogous fashion to MethodH. ESI-MS m/z: 450.2 [M+H]⁺.

Example 54

A solution of 2,4-dichloro-5-nitropyrimidine (250 mg, 1.29 mmol, 1.15eq.) in THF (2 mL) was chilled in a −78° C. bath. To this solution wasslowly added over 40 mins a mixture of compound 1 (335 mg, 1.12 mmol,1.0 eq.) and DIEA (450 μL, 2.58 mmol, 2.3 eq.) in THF (4 mL). Afteraddition was complete, the reaction was stirred at −78° C. during 30-40mins, then allowed to warm slowly to 15° C. over 1 h. The reactionmixture was diluted with DCM (40 mL), washed with water and brine (15 mLeach), dried over Na₂SO₄, and concentrated. This residue was purified byflash chromatography eluting with 300 mL each 10/20/30/40% EtOAc/hexanesto give(S)-8-chloro-3-(1-(2-chloro-5-nitropyrimidin-4-ylamino)ethyl)-2-phenylisoquinolin-1(2H)-one75. ESI-MS m/z: 456.15 [M+H]⁺.

Example 55

Compound 75 (450 mg, 0.99 mmol) was dissolved in THF (45 mL), treatedwith concentrated ammonium hydroxide solution (9 mL), and stirred atambient temperature for 16 h. The solvent was evaporated in vacuo andthe residue suspended in water (50 mL) and brine (20 mL), and extractedwith DCM (3×35 mL). The combined organic layers were washed with brine(15 mL each), dried over Na₂SO₄, and concentrated to afford(S)-3-(1-(2-amino-5-nitropyrimidin-4-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one76, 430 mg (0.99 mmol, quant.). ESI-MS m/z: 437.16 [M+H]⁺.

Example 56

A mixture of 4,6-dichloropyrimidine (200 mg, 1.34 mmol, 1.6 eq.),compound 1 (250 mg, 0.84 mmol, 1.0 eq.), and TEA (350 μL, 2.5 mmol, 3.0eq.) in 1,4-dioxane (7.5 mL) was heated at 60° C. for 3 days. Thereaction was charged with additional 4,6-dichloropyrimidine (100 mg,0.67 mmol, 0.8 eq.) and TEA (175 μL, 1.3 mmol, 1.5 eq.) and heated at80° C. for 16 h. The reaction mixture was diluted with DCM, 5% aqueousacetic acid, and brine (50 mL each), separated, and the organic phasewas washed with 0.1 M NaOH and brine (15 mL each), dried on Na₂SO₄, andconcentrated. The residue was purified by flash chromatography elutingwith 300 mL each 10/20/30/40/50% EtOAc/hexanes to give(S)-8-chloro-3-(1-(6-chloropyrimidin-4-ylamino)ethyl)-2-phenylisoquinolin-1(2H)-one77. ESI-MS m/z: 411.14 [M+H]⁺.

Example 57

A heavy-wall glass tube with stir bar and FEP-encapsulated-siliconeo-ring seal was charged with 77 (ca. 300 mg, 0.73 mmol) in 1,4-dioxane(12 mL) and concentrated ammonium hydroxide solution (10 mL), thensealed tightly and heated at 120° C. After 16 h, more ammonium hydroxide(6 mL) was added and heating continued at 150° C. during 6 h, then 160°C. during 24 h. A third portion of ammonium hydroxide (8 mL) was addedand heating continued at 150° C. during 3 days. The reaction mixture waspoured into a mixture of water and brine (35 mL each), stirred about 1 hat 0° C., and the resulting precipitate collected by filtration andwashed with ice-water. This material was dried in vacuo to give(S)-3-(1-(6-aminopyrimidin-4-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one78. ESI-MS m/z: 392.15 [M+H]⁺.

Example 58

To a mixture of 2-amino-4-chloro-pyrimidine 79 (542 mg, 4.18 mmol) inmethanol (7 mL) and acetonitrile (5 mL), N-iodosuccinimide (941 mg, 4.18mmol) was added and the resulting mixture was stirred at 60° C. for 1.5h. The reaction mixture was allowed to cool to room temperature, treatedwith Et₂O (10 mL) and filtered to afford product 80.

To a mixture of compound 80 (250 mg, 0.979 mmol) and phenyl boronic acid(239 mg, 1.957 mmol) in anhydrous dioxane (5 mL) in a sealed tube,Pd(PPh₃)₄(226 mg, 0.196 mmol) and aqueous Na₂CO₃ solution (1.5 M, 1.30mL, 1.95 mmol) were added and the resulting mixture was stirred at 120°C. for 1.5 h. The reaction mixture was allowed to cool to roomtemperature, quenched with water, and then extracted with ethyl acetate.The combined organic layers were washed with brine, dried over Na₂SO₄and filtered. The filtrate was concentrated in vacuo and the residue wasfurther purified by ISCO column chromatography (silica gel cartridge,10-50% EtOAc-Hexanes) to afford product 81.

To a mixture of compound 81 (69 mg, 0.335 mmol) and compound 1 (100 mg,0.335 mmol) in anhydrous NMP (3 mL) in a sealed tube,diisopropylethylamine (0.234 mL, 1.34 mmol) was added and the resultingmixture was stirred at 160° C. for 20 h. The mixture was allowed to coolto room temperature, quenched with water and extracted with ethylacetate. The combined organic layers were washed with brine, dried overNa₂SO₄ and filtered. The filtrate was concentrated in vacuo and theresidue was purified by ISCO column chromatography (silica gelcartridge, 0-8% MeOH in 1/1 EtOAc/DCM) to afford the product(S)-3-(1-(2-amino-5-phenylpyrimidin-4-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one82. ESI-MS m/z: 468.2 [M+H]⁺.

Example 59

To a mixture of compound 80 (128 mg, 0.502 mmol) and compound 1 (100 mg,0.335 mmol) in anhydrous NMP (3 mL) in a sealed tube,diisopropylethylamine (0.234 mL, 1.34 mmol) was added and the resultingmixture was stirred at 120° C. for 16 h. The mixture was allowed to coolto room temperature, quenched with water and extracted with ethylacetate. The combined organic layers were washed with brine, dried overNa₂SO₄ and filtered. The filtrate was concentrated in vacuo and theresidue was purified by ISCO column chromatography (silica gelcartridge, 10-75% EtOAc/Hexanes) to afford the product 83.

A mixture of compound 83 (40 mg, 0.077 mmol), sodium thiomethoxide (11mg, 0.155 mmol), sodium carbonate (21 mg, 0.155 mmol) and copper iodide(0.7 mg, 0.007 mmol) in IPA (2 mL) in a sealed tube was stirred at 80°C. for 24 h. The reaction mixture was allowed to cool to roomtemperature, quenched with water, and then extracted with ethyl acetate.The combined organic layers were washed with brine, dried over Na₂SO₄and filtered. The filtrate was concentrated in vacuo and the residue wasfurther purified by ISCO column chromatography (silica gel cartridge,10-75% EtOAc-Hexanes) to afford product 84.

To a solution of compound 84 (10 mg, 0.023 mmol) in anhydrous DCM (3mL), m-chloroperbenzoic acid (11 mg, 0.069 mmol) was added and theresulting mixture was stirred at room temperature for 0.5 h. The mixturewas allowed to cool to room temperature, quenched with water andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by ISCO columnchromatography (silica gel cartridge, 0-80% EtOAc/Hexanes) to afford theproduct(S)-3-(1-(2-amino-5-(methylsulfonyl)pyrimidin-4-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one85. ESI-MS m/z: 470.2 [M+H]⁺.

Example 60

To a mixture of 2-amino-4-chloro-6-methylpyrimidine 86 (5.0 g, 34.8mmol) in methanol (70 mL) and acetonitrile (50 mL), N-iodosuccinimide(11.8 g, 52.2 mmol) was added and the resulting mixture was stirred at60° C. for 5 h. The reaction mixture was allowed to cool to roomtemperature, treated with Et₂O (100 mL) and filtered to afford product87.

To a mixture of compound 87 (250 mg, 0.979 mmol) in anhydrous DMF (40mL), copper cyanide (332 mg, 3.71 mmol), copper iodide (247 mg, 1.30mmol) and Pd(PPh₃)₄(1.07 g, 0.928 mmol) were added and the resultingmixture was stirred at 80° C. for 1.5 h. The reaction mixture wasallowed to cool to room temperature, quenched with water, and treatedwith ethyl acetate. The biphasic mixture was filtered on celite andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo and the residue was further purified by ISCOcolumn chromatography (silica gel cartridge, 10-50% EtOAc-Hexanes) toafford product 88.

To a mixture of compound 88 (42 mg, 0.250 mmol) and compound 1 (50 mg,0.167 mmol) in anhydrous DMF (3 mL) in a sealed tube,diisopropylethylamine (0.117 mL, 0.669 mmol) was added and the resultingmixture was stirred at 120° C. for 20 h. The mixture was allowed to coolto room temperature, quenched with water and extracted with ethylacetate. The combined organic layers were washed with brine, dried overNa₂SO₄ and filtered. The filtrate was concentrated in vacuo and theresidue was purified by ISCO column chromatography (silica gelcartridge, 20-100 EtOAc/Hexanes) to afford the product(S)-2-amino-4-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethylamino)-6-methylpyrimidine-5-carbonitrile89. ESI-MS m/z: 431.2 [M+H]⁺.

Example 61

To a stirred mixture of compound 1 (0.335 mmol, 1 eq) and4-chloro-5-iodopyrimidin-2-amine (0.502 mmol, 1.5 eq) in NMP (3_(mL)) at120° C., DIPEA was added and the resulting mixture was stirred at 120°C. overnight and then cooled to room temperature. The mixture waspartitioned between ethyl acetate and brine, washed several times withbrine, dried and concentrated. The product was purified by silica gelcolumn chromatography eluting with ethyl acetate/hexanes to give product83.

To a stirred mixture of 83 (0.044 mmol, 1 eq) and copper(I) iodine (4.44μmol, 0.1 eq) in triethylamine, dichlorobis(triphenylphosphine)palladium (4.44 μmol, 0.1 eq) and TMS-acetylene (0.049 mmol, 6.91 μl)were added. The mixture was degassed for 15 minutes and then stirred for1 h at room temperature. The mixture was extracted with ethyl acetateand washed with brine, and the organic layers were concentrated to giveproduct 90.

To a stirred mixture of 90 in methanol (2 mL), potassium carbonate(10.66 μmol, 0.15 eq) was added. The mixture was stirred under argon atroom temperature for 40 minutes. The mixture was then extracted withethyl acetate and washed with brine. The organic layers were separatedand concentrated under vacuum. The product was purified by silica gelcolumn chromatography eluting with ethyl acetate (from 10 to100%)/hexanes to give product 91. ESI-MS m/z: 416.2 [M+H]⁺.

Example 62

To a stirred mixture of 2-amino-4-chloro-6-methylpyrimidine (0.266 mmol,1.62 eq) and compound 1 (0.164 mmol, 0.164 mmol, 1 eq) in NMP (1.5 ml),DIPEA (0.656 mmol, 4 eq) was added. The mixture was heated to 160° C.for 12 hours. Then the mixture was extracted with ethyl acetate andwashed with water and brine. The product was purified by silica gelcolumn chromatography eluting with DCM/methanol (from 0 to 10%) toafford the product(S)-3-(1-((2-amino-6-methylpyrimidin-4-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one92. ESI-MS m/z: 406.2 [M+H]⁺.

Example 63

Compound 94 was prepared from compound 1 in two steps by Suzuki couplingwith benzo[d][1,3]dioxol-5-ylboronic acid in analogous fashion tocompound 2 in Example 1 to afford compound 93, then coupling to2-amino-4-chloropyrimidine-5-carbonitrile (E-2) (prepared by Method E)according to Method G. ESI-MS m/z: 503.0 [M+H]⁺.

Example 64

Compound 96 was prepared from compound 1 in two steps by Suzuki couplingwithN,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-aminein analogous fashion to compound 2 in Example 1 to afford compound 95,then coupling to 2-amino-4-chloropyrimidine-5-carbonitrile (E-2)(prepared by Method E) according to Method G. ESI-MS m/z: 503.2 [M+H]⁺.

Example 65

Compound 98 was prepared from compound 1 in two steps by Suzuki couplingwith (5-fluoropyridin-3-yl)boronic acid in analogous fashion to compound2 in Example 1 to afford compound 97, then coupling to2-amino-4-chloropyrimidine-5-carbonitrile (E-2) (prepared by Method E)according to Method G. ESI-MS m/z: 478.2 [M+H]⁺.

Example 66

Compound 100 was prepared from compound 1 in two steps by Stillecoupling with 3-methoxy-2-methyl-5-(tributylstannyl)pyridine inanalogous fashion to compound 66 in Example 49 to afford compound 99,then coupling to 2-amino-4-chloropyrimidine-5-carbonitrile (E-2)(prepared by Method E) according to Method G. ESI-MS m/z: 504.2 [M+H]⁺.

Example 67

Compound 102 was prepared from compound 1 in two steps by Suzukicoupling with3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide inanalogous fashion to compound 2 in Example 1 to afford compound 101,then coupling to 2-amino-4-chloropyrimidine-5-carbonitrile (E-2)(prepared by Method E) according to Method G. ESI-MS m/z: 538.0 [M+H]⁺.

Example 68

Amine 103 was prepared from commercially available2-chloro-6-methylbenzoic acid according to Method A. Compound 103 wasthen coupled to 2-amino-4-chloropyrimidine-5-carbonitrile (E-2)according to Method G to afford compound 104. The following Suzukicoupling with (2-methoxypyrimidin-5-yl)boronic acid was in analogousfashion to compound 9 in Example 2 to afford compound 105. ESI-MS m/z:455.2 [M+H]⁺.

Example 69

Compound 104 was prepared as described in Example 68. Suzuki coupling ofcompound 104 with (5-methoxypyridin-3-yl)boronic acid was in analogousfashion to compound 9 in Example 2 to afford compound 106. ESI-MS m/z:454.2 [M+H]⁺.

Example 70

Compound 104 was prepared as described in Example 68. Suzuki coupling ofcompound 104 with ((2-methoxypyridin-4-yl)boronic acid was in analogousfashion to compound 9 in Example 2 to afford compound 107. ESI-MS m/z:454.2 [M+H]⁺.

Example 71

Compound 108 was prepared as described in Example 68. Suzuki coupling ofcompound 104 with (6-methoxypyridin-3-yl)boronic acid was in analogousfashion to compound 9 in Example 2 to afford compound 108. ESI-MS m/z:454.0 [M+H]⁺.

Example 72

Compound 109 was prepared from compound 8 according to Method G.Compound 109 was then converted to compound 110 according to thefollowing procedure: The mixture of (S)-ethyl2-amino-4-((1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carboxylate(300 mg, 0.65 mmol) and 2-methoxypyridin-4-yl)boronic acid (149 mg, 0.98mmol) in 1,4-dioxane:water (3:1, 12 mL) was degassed and backfilled withargon (three cycles). To this mixture,2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (121 mg, 0.26 mmol),palladium(II) acetate (29 mg, 0.13 mmol), and Na₂CO₃ (207 mg, 1.95 mmol)were added sequentially. The resulting mixture was degassed andbackfilled with argon (three cycles), and then stirred at 120° C. for 3h. The mixture was allowed to cool to RT, and then partitioned betweenethyl acetate and water. The organic layer was washed with brine, driedover Na₂SO₄ and filtered. The filtrate was concentrated in vacuo and theresidue was purified by ISCO column chromatography (silica gelcartridge, 0-10% MeOH/DCM) to afford the product 110, (S)-ethyl2-amino-4-((1-(8-(2-methoxypyridin-4-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carboxylate.

To a solution of compound 110 (196 mg, 0.37 mmol) in 1,4-dioxane-water(3:1, 8 mL), sodium hydroxide (73 mg, 1.83 mmol) was added and theresulting mixture was stirred at 50° C. for 1 h. Sodium hydroxide (18mg, 0.46 mmol) was added to the mixture and stirring was continued for16 h. The reaction was allowed to cool to RT, and then concentrated invacuo. The residue was diluted with water and acidified with aqueous HCl(2.0 M) to adjust the pH to 3-4. The mixture was extracted with 10%MeOH-DCM. The organic layer was washed with brine, dried over Na₂SO₄ andfiltered. The filtrate was concentrated in vacuo to afford product 111,(S)-2-amino-4-((1-(8-(2-methoxypyridin-4-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carboxylicacid. ESI-MS m/z: 509.2 [M+H]⁺.

Example 73

To a solution of(S)-2-amino-4-((1-(8-(2-methoxypyridin-4-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)-pyrimidine-5-carboxylicacid (44 mg, 0.087 mmol) in anhydrous N,N-dimethylmethanamide (3 mL),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (25 mg, 0.13 mmol) andhydroxybenzotriazole (18 mg, 0.13 mmol) were added and the resultingmixture was stirred at RT for 30 min. To this mixture, dimethylamine (2Min THF, 0.065 mL, 0.13 mmol) and N,N-diisopropylethylamine (0.040 mL,0.19 mmol) were added and the reaction mixture was stirred at RT for 3h. The mixture was partitioned between water and ethyl acetate. Theorganic layer was washed with brine, dried over Na₂SO₄ and filtered. Thefiltrate was concentrated in vacuo to afford the product 112,(S)-2-amino-4-((1-(8-(2-methoxypyridin-4-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)-N,N-dimethylpyrimidine-5-carboxamide.ESI-MS m/z: 533.8 [M−H]⁺.

Example 74

Compound 113 was prepared from compound 111 in analogous fashion tocompound 112 except that methylamine hydrochloride was used in place ofdimethylamine. ESI-MS m/z: 522.2.0 [M+H]⁺.

Example 75

Compound 114 was prepared from compound 111 in analogous fashion tocompound 112 except that 2-dimethylaminoethanol was used in place ofdimethylamine. ESI-MS m/z: 565.8 [M+H]⁺.

Example 76

Compound 115 was prepared by Suzuki coupling of compound 8 and(5-ethoxypyridin-3-yl)boronic acid according to Example 2. ESI-MS m/z:504.2 [M+H]⁺.

Example 77

Compound 116 was prepared from compound 62 in analogous fashion tocompound 66 in Example 49. ESI-MS m/z: 491.2 [M+H]⁺.

Example 78

To a solution of(S)-2-amino-4-((1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carbonitrile(53) (495 mg, 1.19 mmol) in anhydrous 1,4-dioxane (20 mL), sulfuricacid/water (1:1, 7 mL) was added dropwise. The reaction mixture wasstirred at 90° C. for 60 h. The mixture was allowed to cool to RT andbasified with NaHCO₃. The precipitate was collected by filtration andthen dissolved in water. The resulting mixture was extracted with ethylacetate. The combined organic layers were washed with brine, dried overNa₂SO₄ and filtered. The filtrate was concentrated in vacuo to affordthe product 117,(S)-2-amino-4-((1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carboxylicacid. The material was used directly in the next step.

Compound 117 was converted to compound 118 in analogous fashion tocompound 112 in Example 73. Compound 118 was then converted to 119 bySuzuki coupling with (2-methoxypyridin-4-yl)boronic acid in analogousfashion to compound 8 in Example 2. ESI-MS m/z: 575.9 [M−H]⁻.

Example 79

Compound 121 was synthesized in analogous fashion to B-6 using Method Band 4-fluoroaniline as the amine coupling partner. Compound 121 was thencoupled with 2-amino-4-chloropyrimidine-5-carbonitrile according toMethod G to afford the product 122. ESI-MS m/z: 435.2 [M−H]⁺.

Example 80

A mixture of compound 8 (71.1 mg, 0.17 mmol, 1.0 equiv.), 4-isoxazolepinacol boronate (66.5 mg, 0.34 mmol, 2.0 equiv.), sodium carbonate (90mg, 0.85 mol, 5 equiv.) and Pd-AMPHOS catalyst (24.1 mg, 0.034 mmol, 0.2equiv.) in 1.5 ml degassed 4:1 dioxane-water was heated for 1 h. beforepartitioning between EtOAc and water. The organic layer was collected,the aqueous layer was extracted with EtOAc, and the combined EtOAclayers were washed with brine. The solvent was removed and the residuewas purified on silica gel to provide 124 (ESI-MS m/z: 422.2 [M−H]⁺) anda mixture of 123 and 125. The mixture was then purified by HPLC to give123 (ESI-MS m/z: 450.2 [M−H]⁺) and 125 (ESI-MS m/z: 383.2 [M−H]⁺).

Example 81

Compound 126 was prepared from compound 8 usingN-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamidein the Suzuki reaction according to Method J. ESI-MS m/z: 552.2 [M−H]⁺.

Compound 127 was prepared from compound 8 using3-(N,N-dimethylsulfamoylamino)phenylboronic acid in the Suzuki reactionaccording to Method J. ESI-MS m/z: 552.2 [M−H]⁺.

Example 83

Compound 128 was prepared from compound 1 using4,6-dichloro-5-nitropyrimidine according to Method G. ESI-MS m/z: 456.1[M−H]⁺.

Example 84

Compound 129 was prepared from compound 128 using the procedure toconvert compound 3 to compound 4 in Example 1. ESI-MS m/z: 456.1 [M−H]⁺.

Example 85

Compound 130 was prepared from compound 8 using2-hydroxypyridin-4-ylboronic acid in the Suzuki reaction according toMethod J. ESI-MS m/z: 476.2 [M−H]⁺.

Example 86

4-Chloro-5-(pyridin-3-yl)pyrimidin-2-amine 131 was prepared from thecoupling of 4-chloro-5-iodopyrimidin-2-amine with pyridin-3-ylboronicacid as follows: the amine (150 mg, 0.587 mmol), and the boronic acid(144 mg, 1.174 mmol) were suspended in dioxane (2.5 mL) and Na₂CO₃ (783μl, 1.174 mmol). The mixture was bubbled with Ar for 5 min then chargedwith Pd(Ph₃P)₄ (136 mg, 0.117 mmol). The mixture was stirred at 90° C.for 2 h, then cooled to room temperature. The mixture was partitionedbetween EtOAc and water. The organic layer was dried, filtered, andconcentrated to give a residue which was purified by silica gel columnchromatography to give 4-chloro-5-(pyridin-3-yl)pyrimidin-2-amine 131.

Compound 132 was prepared from 1 using4-chloro-5-(pyridin-3-yl)pyrimidin-2-amine in the coupling reactionaccording to Method G. Compound 133 was prepared from 132 using2-methoxypyridin-4-ylboronic acid in the Suzuki reaction according toMethod J.

Example 87

To a mixture of 2-amino-4-chloro-pyrimidine 79 (10.2 g, 79 mmol) inmethanol (140 mL) and acetonitrile (100 mL), N-bromosuccinimide (14.01g, 79 mmol) was added, and the resulting mixture was stirred at RT forabout 0.5 h. The reaction mixture was treated with Et₂O (200 mL), thencooled to about 5° C. and stirred for about 1 h. The mixture wasfiltered and the product air dried to afford compound 134.

To a mixture of compound 134 (4.83 g, 23.23 mmol) and compound 1 (5.34g, 17.87 mmol) in anhydrous n-butanol (80 mL), diisopropylethylamine(6.93 g, 053.6 mmol) was added, and the resulting mixture was stirred atabout 115° C. for about 36 hrs. The mixture was allowed to cool to RTand concentrated in vacuo. The residue was suspended in toluene (100 mL)and concentrated in vacuo. The resulting product was suspended intoluene and heated to reflux, then cooled to about 5° C. over about 2hrs. The resulting suspension was filtered, the solids washed with coldtoluene, then air dried to afford the product 135. ESI-MS m/z: 470.0[M+H]⁺.

Example 88

A mixture of compound 135 (125 mg, 0.266 mmol) and4-methyl-2-(tribyulstannyl)thiazole (129 mg, 0.332 mmol) in anhydroustoluene (2 mL) in a sealed tube was degassed by bubbling Ar for 5 min.The mixture was charged with Pd(PPh₃)₄(31 mg, 0.027 mmol) and theresulting mixture was stirred at 90° C. for 15 hrs. The reaction mixturewas allowed to cool to room temperature, filtered, washed with tolueneand the filtrate was concentrated in vacuo. The residue was purified bycolumn chromatography (silica gel cartridge, 0-10% MeOH in 1/1EtOAc-DCM). The residue was further purified by semi-prep HPLC(ACN/water/ammonium bicarbonate) to affort product 136. ESI-MS m/z:489.1 [M+H]⁺.

Example 89

Compound 137 was prepared from compound 135 using2-ethoxy-4-(tributylstannyl)thiazole in analogous fashion to compound136 in Example 88. Compound 137 (60.5 mg, 0.117 mmol) and1-methyl-6-oxo-1,6-dihydropyridin-3-ylboronic acid (54.8 mg, 0.233 mmol)were dissolved in dioxane (2 mL) and Na₂CO₃ aq. (0.155 ml, 0.233 mmol).The mixture was bubbled with Ar for 5 min then charged withPdCl₂(amphos)₂ (20.63 mg, 0.029 mmol). The mixture was heated to 80° C.for 2 h. The reaction was cooled to room temperature and poured into asaturated sodium bicarbonate/EtOAc mixture. The layers were separatedand the organic layer was dried over Na₂SO₄, filtered and concentrated.The residue was purified by HPLC to give the product 138. ESI-MS m/z:592.3 [M+H]⁺.

Example 90

Compound 139 was prepared from compound 135 using2-methoxy-5-(tributylstannyl)thiazole in analogous fashion to compound136 in Example 88. Compound 140 was prepared from compound 139 using2-methoxypyridin-4-ylboronic acid in analogous fashion to compound 138in Example 89. ESI-MS m/z: 578.3 [M+H]⁺.

Example 91

A flask was charged with compound 141 (350 mg, 0.88 mmol),bis(pinacolato)diboron (668 mg, 2.6 mmol), Pd₂(dba)₃ (24 mg, 0.026mmol), X-phos (25 mg, 0.06 mmol) and potassium acetate (258 mg, 2.6mmol). The flask was evacuated and filled with Ar. 4 mL of degasseddioxane (bubbling N₂ for 15 min) was added, and the reaction was stirredat 110° C. for 8 h, then cooled to room temperature. The mixture wasdiluted with ethyl acetate (50 ml) and washed with water (15 ml) andbrine and dried. The material was purified with a combiflash silica gelcolumn to give 320 mg of pinacol boronate ester 142.

To a mixture of compound 142 (320 mg, 0.65 mmol) in THF (10 mL) wasadded 1M NaOH (2 mL, 2.0 mmol), followed by 30% H₂O₂/H₂O (0.67 mL, 6.5mmol), and the mixture was stirred for 2 h. The mixture was then diluted(EtOAc, 50 mL), washed with H₂O (20 mL), brine, dried and concentrated.Combiflash purification (30% EtOAc) gave phenol 143 (105 mg).

To phenol 143 (40 mg, 0.1 mmol) was added 1.25 M HCl (2.52 mL, 3.15mmol) and the mixture stirred for 4 h at 50 C. The mixture was cooled toroom temperature, MeOH was removed by evaporation, and the residue wasdiluted with 20 ml DCM. Saturated sodium bicarbonate (5 mL) was added,and the mixture was stirred at room temperature for 1 h. The organiclayer was separated from the aqueous layer, and the aqueous layer wasextracted with DCM (20 ml). The combined organic layers were dried,filtered, and concentrated to give the amine 144 (26 mg), which wasdirectly used in next step without purification. The amine 144 wastreated with 2-amino-4-chloropyrimidine-5-carbonitrile in analogousfashion to Method G to afford product 145. ESI-MS m/z: 399.3 [M+H]⁺.

Example 92

To a de-oxygenated suspension of potassium carbonate (65 mg, 0.47 mmol)and dimethyl sulfate (60 mg, 0.47 mmol) in acetone (5 ml) under nitrogenwas added compound 143 (30 mg. 0.07 mmol) in de-oxygenated acetone (4ml). The mixture was heated at reflux under nitrogen for 5 h, thenmethanol (10 ml) was added and the mixture was refluxed for a furtherhour. The mixture was filtered and concentrated, and flashchromatography on silica gel gave 26 mg of ether 146. Compound 146 wasconverted to compound 147 in a similar manner as compound 143 in Example91 to give amine 146, which was coupled to2-amino-4-chloropyrimidine-5-carbonitrile using Method G to give product148. ESI-MS m/z: 413.3 [M+H]⁺.

Example 93

A flask was charged with compound 143 (30 mg, 1 equiv), Cu(OAc)₂ (29 mg,2 equiv), phenylboronic acid (20 mg, 2 equiv), and powdered 4 Å MS (15mg). The mixture was diluted with DCM (8 ml) and Et₃N (33 μl, 3 equiv)was added. The reaction was stirred at room temperature for 3 days. Themixture was filtered through a bed of celite/silica. The combinedfiltrate was concentrated to give product 149 (25 mg), which was useddirectly in next step. Compound 149 was converted in a similar manner as143 in Example 91 to give amine 150, which was coupled to2-amino-4-chloropyrimidine-5-carbonitrile using Method G to give product151. ESI-MS m/z: 475.3 [M+H]⁺.

Example 94

To a mixture of 3-bromopyridol (870 mg, 5 mmol, 1 equiv.), aqueous KOH(21 mL, 30% solution, 105 mmol, 21 equiv.) in 20 mL acetonitrile in apressure vessel at −78° C. was added 2-chloro-2,2-difluoroacetophenone.The vessel was sealed and heated at 80° C. for 4 h before cooling anddiluting with 50 mL MTBE. The organic layer was collected, the aqueouslayer was extracted with MTBE (2×50 mL), and the combined organic layerswere washed with water (50 mL), brine (50 mL), and dried over sodiumsulfate. Then, the solvents were removed in vacuo and the residue waspurified on silica gel (12 g, ISCO) using 0→20% EtOAc-hexanes to give K(488 mg).

A mixture of K (475 mg, 2.12 mmol), bis(pinacolato)diboron (808 mg, 3.18mmol, 1.5 equiv.) and PdCl₂(dppf) DCM adduct (87 mg, 0.106 mmol. 0.05equiv.) and potassium acetate (666 mg, 6.8 mmol, 3.2 equiv.) in 10 mLdioxane was heated for 1 h. The mixture was cooled, concentrated invacuo, diluted with DCM and filtered through a pad of celite. The filtercake was washed with 4×10 mL DCM, and the combined DCM layers wereconcentrated in vacuo. The residue was purified on silica gel (12 g,ISCO) using 0→50% acetone-DCM to give 312 mg of product L.

A mixture of compound 8 (70 mg, 0.219 mmol, 1 equiv.), compound L (150mg, 60%, 0.332 mmol, 2 equiv.) sodium carbonate (89 mg, 0.84 mmol, 5equiv.) and Pd-AMPHOS catalyst (17.8 mg, 0.025 mmol, 0.15 equiv.) in 1.8mL of degassed 4:1 dioxane-water was sparged with argon for 2 min. Themixture was sealed and heated at 100° C. for 1 h, cooled, and dilutedwith 10 mL each EtOAc and water. The organic layer was collected, theaqueous layer was extracted with EtOAc (3×10 mL), the combined EtOAclayers were washed with water (10 mL), brine (10 mL), dried over sodiumsulfate and the solvents were removed in vacuo. The residue was purifiedon silica gel using 0-70% acetone in DCM to give compound 152. ESI-MSm/z: 526.3 [M+H]⁺.

Example 95

Compound 153 was prepared from compound 8 using Method J as described inExample 94 withN-methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamidein the Suzuki reaction. ESI-MS m/z: 566.3 [M+H]⁺.

Example 96

Compound 154 was prepared from compound 111 in analogous fashion tocompound 112 in Example 73, where azetidine hydrochloride was used inplace of dimethylamine. ESI-MS m/z: 547.8 [M+H]⁺.

Example 97

Compound 155 was prepared from compound 111 in analogous fashion tocompound 112 in Example 73, where ethylmethylamine was used in place ofdimethylamine. ESI-MS m/z: 549.8 [M+H]⁺.

Example 98

Compound 156 was prepared from compound 8 using6-hydroxypyridin-3-ylboronic acid according to Method J. ESI-MS m/z:549.8 [M+H]⁺.

Example 99

Bromide 135 (100 mg, 0.212 mmol) and3-(piperidin-1-ylsulfonyl)phenylboronic acid (86 mg, 0.319 mmol) weredissolved in dioxane (2 mL) and Na₂CO₃ aq. (283 μl, 0.425 mmol). Themixture was bubbled with Ar for 5 min then charged with Pd(Ph₃P)₄ (12mg, 10.6 μmol). The mixture was heated to 90° C. for 3 h. The reactionwas cooled to room temperature, and poured into a saturatedbicarbonate/EtOAc mixture. The phases were split and the organic layerwas dried, filtered and pre-adsorbed on SiO₂. The residue was purifiedon SiO₂ (0-90 Acetone/DCM) to give the sulfonamide 157. ESI-MS m/z:615.3 [M+H]⁺.

Example 100

Compound 158 was prepared from compound 135 using3-fluoro-4-hydroxyphenylboronic acid according to Example 99. Compound159 was prepared from compound 158 using 2-methoxypyridin-4-ylboronicacid according to Example 89. ESI-MS m/z: 475.3 [M+H]⁺.

Example 101

Compound 160 was prepared from compound 135 using3-fluoro-5-hydroxyphenylboronic acid according to Example 99. Compound161 was prepared from compound 160 using 2-methoxypyridin-4-ylboronicacid according to Example 89. ESI-MS m/z: 475.3 [M+H]⁺.

Example 102

Compound 162 was prepared from compound 135 using4-fluoro-3-hydroxyphenylboronic acid according to Example 99. Compound163 was prepared from compound 162 using 2-methoxypyridin-4-ylboronicacid according to Example 89. ESI-MS m/z: 475.2 [M+H]⁺.

Example 103

Compound 164 was prepared from compound 8 using3-(methylsulfonyl)phenylboronic acid according to Method J. ESI-MS m/z:535.2 [M+H]⁺.

Example 104

Compound 165 was prepared from compound 8 using3-(methylsulfonyl)phenylboronic acid according to Method J. ESI-MS m/z:535.2 [M+H]⁺.

Example 105

Compound 166 was prepared from compound 8 using2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineaccording to Method J. ESI-MS m/z: 490.2 [M+H]⁺.

Example 106

Compound 167 was prepared from compound 8 using4-(methylsulfonamido)phenylboronic acid according to Method J. ESI-MSm/z: 552.2 [M+H]⁺.

Example 107

Compound 168 was prepared from compound 135 using pyridin-4-ylboronicacid according to Example 99. Compound 169 was prepared from compound168 using 2-methoxypyridin-4-ylboronic acid according to Example 89.ESI-MS m/z: 542.3 [M+H]⁺.

Example 108

5-amino-2,4-dichloropyrimidine (100 mg, 0.7 mmol) was dissolved in 10 mLof DCM at 0° C. The cooled solution was treated with triethylamine (340μl, 4 equiv) followed by slow addition of methylsulfonyl chloride (80μl, 1.7 equiv). The mixture was stirred for 4 h at room temperature.Then the mixture was concentrated in vacuo, and compound 1 (182 mg) wasadded. NMP (6 mL) was added and the reaction was heated to 120° C.overnight. The reaction was diluted in EtOAc (50 ml), washed with water(4×30 ml), brine, and the organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated. The resulting compound 170 was subjected toaminolysis according to Method E to afford the product 171. ESI-MS m/z:485.1 [M+H]⁺.

Example 109

5-amino-2,4-dichloropyrimidine (100 mg, 0.7 mmol) was dissolved in 10 mLof DCM at 0° C. The cooled solution was treated with triethylamine (340μl, 4 equiv) followed with slow addition of acetyl chloride (45 μl, 1equiv). The mixture was stirred for 4 h at room temperature. Then thesolvent was evaporated under reduced pressure, and compound 1 (182 mg)was added. NMP (6 mL) was added and the reaction was heated to 120° C.overnight. The reaction was diluted in EtOAc (50 ml), washed with water(4×30 ml), brine, and the organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated. The resulting compound 172 was subjected toaminolysis according to Method E to give the product 173. ESI-MS m/z:449.1 [M+H]⁺.

Example 110

5-amino-2,4-dichloropyrimidine (85 mg, 0.6 mmol) was dissolved in 10 mLof DCM at 0° C. The cooled solution was treated with triethylamine (108μl, 1.5 equiv) followed with slow addition of benzoyl chloride (60 μl, 1equiv). The mixture was stirred for 4 h at room temperature. Then thesolvent was evaporated under reduced pressure, and compound 1 (155 mg)was added. NMP (6 mL) was added and the reaction was heated to 120° C.overnight. The reaction was diluted in EtOAc (50 ml), washed with water(4×30 ml), brine, and the organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated. The resulting compound 174 was subjected toaminolysis according to Method E to give the product 175. ESI-MS m/z:511.2 [M+H]⁺.

Example 111

Compound 176 was prepared from compound 1 using4-chloro-5-nitropyrimidin-2-amine according to Method G. Compound 177was prepared from compound 176 using 2-methoxypyridin-4-ylboronic acidin a Suzuki reaction according to Method J. ESI-MS m/z: 510.2 [M+H]⁺.

Example 112

Compound 178 was prepared from compound 135 using phenylboronic acidaccording to Example 99. Compound 179 was prepared from compound 158using 2-methoxypyridin-4-ylboronic acid according to Method J. ESI-MSm/z: 541.2 [M+H]⁺.

Example 113

Compound 180 was prepared from compound 135 using2-methyl-5-(tributylstannyl)thiazole according to Example 88. Compound181 was prepared from compound 180 using 2-methoxypyridin-4-ylboronicacid according to Method J. ESI-MS m/z: 562.3 [M+H]⁺.

Example 114

Compound 182 was prepared from compound 8 using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-oneaccording to Method J. ESI-MS m/z: 490.2 [M+H]⁺.

Example 115

Compound 183 was prepared from compound 8 using1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-oneaccording to Method J. ESI-MS m/z: 490.2 [M+H]⁺.

Example 116

Compound 185 was prepared from compound 8 usingN-methyl-4-(tributylstannyl)pyridin-2-amine in analogous fashion topreparation of compound 69 from compound 62 in Example 51. ESI-MS m/z:489.2 [M+H]⁺.

Example 117

Compound 187 was prepared from compound 8 using4-(tributylstannyl)pyridin-2-amine in analogous fashion to preparationof compound 69 from compound 62 in Example 51. ESI-MS m/z: 475.2 [M+H]⁺.

Example 118

Compound 189 was prepared from compound 8 using2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineaccording to Method J. ESI-MS m/z: 538.2 [M+H]⁺.

Example 119

A mixture of 8 (50 mg), Pd₂(dba)₃ (4 mg), X-Phos (4 mg), KOAc (40 mg),and bis(pinacolato)diboron (100 mg) in degassed 1,4-dioxane (2 mL) wasstirred at 90° C. overnight. The mixture was cooled to room temperatureand diluted with EtOAc (50 mL) and washed 2×25 mL water. The organiclayer was washed with brine, dried over Na₂SO₄, filtered andconcentrated to give a residue that was purified by normal phase columnto give compound 190. Compound 190 was coupled withN-(5-bromopyridin-3-yl)methanesulfonamide according to Method J to giveCompound 191. ESI-MS m/z: 553.2 [M+H]⁺.

Example 120

Compound 192 was prepared from compound 8 using2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineaccording to Method J. ESI-MS m/z: 520.3 [M+H]⁺.

Example 121

A mixture of dichlorobis(acetonitrile) Pd (9.0 mg, 0.035 mmol, 0.185equiv.), X-Phos (51.1 mg, 0.11 mmol, 0.57 equiv.) and cesium carbonate(159 mg, 0.49 mmol, 2.6 equiv.) under argon was added 2 mLpropionitrile. Compound 8 (78 mg, 0.187 mmol, 1 equiv.) was addedfollowed by N-(4-pentynoyl)morpholine in 2 mL propionitrile (0.18 mL,1.18 mmol, 6 equiv.). 2 mL propionitrile was added to the mixture whichwas stirred for 0.5 h at room temp. before heating at 100° C. for 1 h.The mixture was cooled, diluted with EtOAc (10 mL) and water (10 mL).The aqueous layer was extracted with EtOAc (3×10 mL), the combinedorganic layers were washed with water (2×10 mL), brine (10 mL), driedover sodium sulfate and the solvents were evaporated in vacuo. Theresidue was purified on silica gel using 0→5% methanol in DCM to givecompound 193. ESI-MS m/z: 548.3 [M+H]⁺.

Example 122

To a mixture of dichlorobis(acetonitrile) Pd (13.8 mg, 0.053 mmol, 0.05equiv.), X-Phos (76.2 mg, 0.16 mmol, 0.15 equiv.) and cesium carbonate(901 mg, 2.77 mmol, 2.5 equiv.) under argon was added 2 mL acetonitrile.Compound 141 (441 mg, 1.1 mmol, 1 equiv.) was added followed bytrimethylsilyl acetylene in 1 mL acetonitrile (0.184 mL, 1.3 mmol, 1.2equiv.). 2 mL of acetonitrile was added to the mixture and was stirredfor 5 min at room temp. before heating at 90° C. for 2 h. The mixturewas cooled, diluted with 25 mL EtOAc, 5 mL water, and filtered through apad of celite. The organic layer was collected, the aqueous layer wasextracted with EtOAc (2×25 mL), the combined filtrates were washed withwater (2×20 mL), brine (10 mL), dried over sodium sulfate and thesolvents were evaporated in vacuo. The residue was purified on silicagel using 10→85% EtOAc-Hexanes to give 201 mg of compound 195.

A mixture of compound 195 (110 mg, 0.24 mmol, 1 equiv.),azidotrimethylsilane (138 mg, 1.2 mmol, 5 equiv.), sodium ascorbate (0.5mL, 0.02 M in water), and CuSO₄ (0.1 mL, 0.5 M in water) in 3 mL DMSOwas heated at 80° C. for 17 h. The mixture was cooled, partitionedbetween 5 mL 10% citric acid and 10 mL DCM, and the aqueous layer wasextracted with DCM (4×10 mL). The combined organic layers were washedwith 10 mL 5% ammonia, 10 mL water, 10 mL brine, dried over sodiumsulfate and the solvents were evaporated in vacuo. The residue waspurified on silica gel using 0→50% acetone in DCM to give 29 mg ofcompound 195.

A solution of compound 195 (25 mg, 0.05 mmol, 1 equiv.) in 2 mL DCM at22° C. was treated with two portions of TFA (2×80 uL, 2×1 mmol, 40equiv) for one hour each. The mixture was concentrated in vacuo,co-evaporated with 10 mL DCM and then 10 mL hexanes. The residue wasdissolved in 1 mL NMP, and N,N-diisopropylethylamine (20 μL, 2 equiv.)was added followed by 2-amino-4-chloro-5-cyanopyrimidine. The mixturewas heated in a sealed tube at 110° C. for 15 h, cooled and treated withTBAF (2×200 μL, 1.0 M in THF, 0.4 mmol, 8 equiv.) and stirred for 4.5 h.The mixture was diluted with water (10 mL), and extracted with DCM (5×5mL). The combined organic layers were washed with 10 mL brine, driedover sodium sulfate, filtered, and the solvent was removed in vacuo. Theresidue was purified by preparative HPLC to give compound 196. ESI-MSm/z: 450.2 [M+H]⁺.

Example 123

Compound 198 was prepared from compound 197 by ester hydrolysis inanalogous fashion to Example 72. Compound 199 was prepared from compound198 using dimethylamine in analogous fashion to Example 73. ESI-MS m/z:463.0 [M−H]⁺.

Example 124

Compound 201 was prepared from compound 200 according to Method G.Compound 201 was then converted to 203 in 2 steps in analogous fashionto Example 123. ESI-MS m/z: 509.2 [M+H]⁺.

Example 125

Compound 204 was prepared from compound 202 in analogous fashion toExample 124 except that azetidine hydrochloride was used in place ofdimethylamine. ESI-MS m/z: 521.2 [M+H]⁺.

Example 126

Compound 166 was prepared from compound 8 using2-methoxypyridyl-6-boronic acid according to Method J. Compound 205 wasprepared from Compound 166 in analogous fashion to Example 6, exceptBBr₃ was used in place of PBr₃. ESI-MS m/z: 476.2 [M+H]⁺.

Example 127

Compound 206 was prepared from compound 8 using5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineaccording to Method J. ESI-MS m/z: 490.2 [M+H]⁺.

Example 128

4-Pentynoic acid (500 mg, 5.1 mmol), EDCI (1.56 g, 7.7 mmol) and HOBt(1.411 g, 10.2 mmol) were dissolved in 20 mL of DCM under inertatmosphere. A mixture of pyrrolidine (850 uL, 10.2 mmol) and DIPEA (4.5mL, 25.5 mmol) in 3 mL DCM was added and the mixture was stirred for 2h. The mixture was quenched with 25 mL 10% citric acid, stirred for 5min., the organic layer was collected and the aqueous layer wasextracted with 2×20 mL DCM. The combined organic layers were washed with20 mL 10% citric acid. The DCM layer was washed with 20 mL saturatedsodium bicarbonate, 20 mL brine and dried over sodium sulfate. Thefiltrates were concentrated and the residue was adsorbed on silica geland chromatographed on silica gel (12 g) using 0→20% EtOAc-DCM to give620 mg of 1-(pyrrolidin-1-yl)pent-4-yn-1-one.

To dichlorobis(acetonitrile)Pd (7.2 mg, 0.028 mmol), X-Phos (40.1 mg,0.084 mmol), cesium carbonate (167 mg, 0.513 mmol) was addedpropionitrile (3 mL) under argon, and the mixture was stirred for 1 min.Then 1-(pyrrolidin-1-yl)pent-4-yn-1-one (74 mg, 0.178 mmol) was addedunder a positive pressure of argon. A solution of the compound 8 (97 mg,0.642 mmol) in 1 mL propionitrile was added dropwise, then the mixturewas stirred at 100-105° C. for 3 h. The mixture was cooled to roomtemperature, diluted with 20 mL ethyl acetate, filtered through a pad ofcelite and the filter pad was washed with ethylacetate (3×20 mL). Thecombined filtrates were washed with water (20 mL) and brine (10 mL),then dried over sodium sulfate, filtered, and the filtrates wereconcentrated under reduced pressure. The residue was purified on silicagel (12 g) using 0→10% Methanol-DCM) to give compound 207. ESI-MS m/z:532.3 [M+H]⁺.

Example 129

Compound 209 was synthesized from compound B-4 according to Method Busing 4-trifluromethoxyaniline. Compound 210 was prepared from compound209 according to Method G. ESI-MS m/z: 501.2 [M+H]⁺.

Example 130

Compound 211 was prepared from compound 1 using4-chloro-6-methoxypyrimidin-2-amine according to Method G. ESI-MS m/z:422 [M+H]⁺.

Example 131

Compound 214 was prepared from compound B-4 in analogous fashion toExample 129 except that 4-methoxyaniline was used in place of4-trifluoromethoxyaniline. ESI-MS m/z: 447.1 [M+H]⁺.

Example 132

Compound 217 was prepared from compound B-4 in analogous fashion toExample 129 except that 4-chloroaniline was used in place of4-trifluoromethoxyaniline. ESI-MS m/z: 453.0 [M+H]⁺.

Example 133

Compound 220 was prepared from compound B-4 in analogous fashion toExample 129 except that 4-cyanoaniline was used in place of4-trifluoromethoxyaniline. ESI-MS m/z: 442.1 [M+H]⁺.

Example 134

Compound 222 was prepared from compound 8 using tributyl(1-propynyl)tinaccording to Method I. ESI-MS m/z: 421.6 [M+H]⁺.

Example 135

Compound 223 was prepared from compound 135 in analogous fashion toExample 88 except 2-methoxy-4-(tributylstannyl)thiazole was used inplace of 4-methyl-2-(tribyulstannyl)thiazole. ESI-MS m/z: 505.2 [M+H]⁺.

Example 136

Compound 223 was prepared from compound 135 in analogous fashion toExample 88 except 2-(tributylstannyl)thiazole was used in place of4-methyl-2-(tribyulstannyl)thiazole. ESI-MS m/z: 475.1 [M+H]⁺.

Example 137

A mixture of 2-chloro-6-methoxypyrazine (500 mg, 3.46 mmol, 1.0 eq),bis(pinacolato)diboron (1.05 g, 4.13 mmol, 1.2 eq), Pd₂(dba)₃ (95 mg,0.1 mmol, 0.029 eq), P(Cy)₃ (120 mg, 0.43 mmol, 0.13 eq), and potassiumacetate (600 mg, 6.11 mmol, 1.77 eq) in 1,2-dimethoxyethane (10 mL) wasirradiated under argon at 150° C. in a microwave oven for 3 h. Themixture was allowed to cool to RT, quenched with water and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over Na₂SO₄ and filtered. The filtrate was concentrated in vacuoto afford the pinacol ester (600 mg). Compound 1 was prepared fromcommercially available 2-chloro-6-methylbenzoic acid according to MethodA.

To a mixture of compound 1 (200 mg, 0.67 mmol) and the pinacol ester(300 mg, 1.27 mmol) in 1,4-dioxane and water (15 mL and 5 mL),PdCl₂(dppf) (50 mg, 0.068 mmol, 0.1 eq) and Na₂CO₃ (300 mg, 2.83 mmol,4.21 eq) were added and the resulting mixture was stirred at 120° C. for16 h. The reaction mixture was allowed to cool to RT, quenched withwater, and then extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over Na₂SO₄ and filtered. Thefiltrate was concentrated in vacuo and the residue was purified by flashchromatography on silica gel (0-5% MeOH-DCM) to afford compound 225.

Compound 225 was coupled to 2-amino-4-chloropyrimidine-5-carbonitrile(E-2) to afford compound 226 according to Method G. ESI-MS m/z: 490.8[M+H]⁺.

Example 138

A mixture of 2-chloro-5-methoxypyrimidine (1.5 g, 6.38 mmol, 1.0 eq),bis(tri-butyltin) (4.07 g, 7.01 mmol, 1.1 eq), Pd(PPh₃)₄(368 mg, 0.319mmol, 0.05 eq) in toluene (20 mL) was stirred under argon at reflux for15 h. The mixture was allowed to cool to RT and then filtered. Thefiltrate was concentrated in vacuo and the residue was purified by flashchromatography on silica gel (0-5% MeOH-DCM) to afford thetri-butylstannane. Compound 8 was prepared from compound 1 and (E-2)using Method G.

A mixture of compound 8 (100 mg, 0.24 mmol),2-(tributylstannyl)-5-methoxypyrimidine (200 mg, 0.50 mmol, 2.08 eq),bis(tri-t-butylphosphine)palladium(0) (30 mg, 0.059 mmol, 0.25 eq) andCsF (100 mg, 0.66 mmol, 2.74 eq) in 1,4-dioxane (10 mL) was stirredunder argon at reflux for 16 h. The mixture was allowed to cool to RT,poured into water (20 mL) and extracted with ethyl acetate (15 mL×2).The combined organic layers were washed with brine, dried over Na₂SO₄and filtered. The filtrate was concentrated in vacuo and the residue waspurified by flash column chromatography on silica gel (0-5% MeOH-DCM) toafford compound 228. ESI-MS m/z: 491.3 [M+H^(]+).

Example 139

A mixture of 2-chloro-4-methoxypyrimidine (1.0 g, 6.92 mmol, 1.0 eq),bis(tri-butyltin) (5.0 g, 8.62 mmol, 1.24 eq), Pd(PPh₃)₄(200 mg, 0.17mmol, 0.025 eq) and Pd(dppf)Cl₂ (50 mg, 0.068 mmol, 0.01 eq) in toluene(20 mL) under argon was stirred at reflux for 15 h. The mixture wasallowed to cool to RT and filtered. The filtrate was concentrated invacuo and the residue was purified by flash chromatography on silica gel(0-5% MeOH-DCM) to afford the tri-butylstannane. Compound 8 was preparedfrom compound 1 and (E-2) using Method G.

Compound 8 was coupled to the tri-butylstannane in analogous fashion toExample 138 to afford the product 229. ESI-MS m/z: 491.3[M+H^(]+).

Example 140

To a suspension of NaH (60% dispersion in mineral oil, 1.34 g, 0.056mol) in THF (10 mL), a solution of 5-bromopyridin-2-ol (2.5 g, 0.014mol) in THF (50 mL) was added and the resulting mixture was stirred atRT for 1 h. To this mixture, iodoethane (10.9 g, 0.07 mol) was added andthe mixture was stirred at RT overnight. The mixture was quenched withwater and washed with NH₄Cl solution. The organic phase was separated,then concentrated in vacuo and the residue was purified by flashchromatography on silica gel (50-100% PE-AE) to afford5-bromo-1-ethylpyridin-2(1H)-one.

To a suspension of 5-bromo-1-ethylpyridin-2(1H)-one (250 mg, 1.23 mmol)in 1,4-dioxane (15 mL), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane (346.4 mg, 1.35 mmol), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (100 mg, 0.12 mmol) andpotassium acetate (301.4 mg, 3.08 mmol) were added. The reaction mixturewas stirred at reflux for 3 h. The resulting mixture was concentrated invacuo, and the residue was purified by column chromatography on silicagel (10-100% PE-AE) to afford1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one.

Compound 8 (100 mg, 0.24 mmol),1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(89.7 mg, 0.361 mmol),1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (19.58 mg,0.024 mmol) and sodium carbonate (127.2 mg, 1.2 mmol) were suspended in1,4-dioxane (5 mL) and water (1 mL) under argon, and the resultingmixture was stirred at reflux overnight. The resulting mixture wasconcentrated in vacuo, and the residue was purified by columnchromatography on silica gel (0-5% MeOH-DCM) to afford compound 230.ESI-MS m/z: 504.3 [M+H]⁺.

Example 141

To a suspension of NaH (60% dispersion in mineral oil, 1.02 g, 42.4mmol) in THF (10 mL), a solution of 5-bromopyridin-2-ol (2.0 g, 10.6mmol) in THF (50 mL) was added, and the resulting mixture was stirred atRT for 1 h. To this mixture, iodomethane (7.5 g, 53.2 mmol) was addedand the resulting mixture was stirred at RT overnight. The mixture wasquenched with water and extracted with ethyl acetate (200 mL). Theorganic layer was washed with aqueous NH₄Cl solution and dried overanhydrous MgSO₄ and filtered. The filtrate was concentrated to drynessto afford 5-bromo-1,3-dimethylpyridin-2(1H)-one.

The pinacol ester was prepared in analogous fashion to Example 140,except 5-bromo-1,3-dimethylpyridin-2(1H)-one was used in place of5-bromo-1-ethylpyridin-2(1H)-one. Compound 231 was prepared fromcompound 8 in analogous fashion to Example 140, except1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-onewas used in place of1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one.ESI-MS m/z: 504.3 [M+H]⁺.

Example 142

To a solution of 5-bromopyridin-2-ol (1.0 g, 5.75 mmol) in DMF (10 mL)at RT, potassium tert-butoxide (0.68 g, 6.07 mmol) was added and themixture was stirred for 30 min. To this mixture,(bromomethyl)cyclopropane (1.03 g, 8.62 mmol) was added, and theresulting mixture was stirred at 70° C. for 2 h. The mixture was allowedto cool to RT, diluted with EtOAc (50 mL) and quenched with water (20mL). The organic layer was washed with water (2×20 mL) and brine (20mL), dried over anhydrous MgSO₄ and filtered. The filtrate wasconcentrated in vacuo to afford5-bromo-1-(cyclopropylmethyl)pyridin-2(1H)-one.

1-(Cyclopropylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-onewas prepared in analogous fashion to Example 140, except5-bromo-1-(cyclopropylmethyl)pyridin-2(1H)-one was used in place of5-bromo-1-ethylpyridin-2(1H)-one. Compound 232 was prepared fromcompound 8 in analogous fashion to Example 140, except1-(cyclopropylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-onewas used in place of1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one.ESI-MS m/z: 530.3 [M+H]⁺.

Example 143

5-Bromo-1-cyclopentylpyridin-2(1H)-one was prepared from5-bromopyridin-2(1H)-one in analogous fashion to Example 142, except1-bromocyclopentpane was used in place of (bromomethyl)cyclopropane.1-Cyclopentyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-onewas prepared from 5-bromo-1-cyclopentylpyridin-2(1H)-one according toExample 140. Coupling of compound 8 with1-cyclopentyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-onewas performed according to Example 40 to afford product 233. ESI-MS m/z:544.4 [M+H]⁺.

Example 144

Compound 234 was prepared in analogous fashion to Example 143, exceptthat 5-bromo-1-isopropylpyridin-2(1H)-one was used in place of5-bromo-1-cyclopentylpyridin-2(1H)-one. ESI-MS m/z: 518.3 [M+H]⁺.

Example 145

Compound 234 was prepared in analogous fashion to Example 143, exceptthat 5-bromo-1-(tetrahydro-2H-pyran-4-yl)pyridin-2(1H)-one was used inplace of 5-bromo-1-cyclopentylpyridin-2(1H)-one. ESI-MS m/z: 560.4[M+H]⁺.

Example 146

To a stirred mixture of compound 236 (33 g, 174.6 mmol, 1 eq) inanhydrous dichloromethane (500 mL) at −5° C., triethylamine (58 g, 576mmol, 3.3 eq) was added dropwise over 20 min while keeping the reactiontemperature between −5° C. to 0° C. during the addition. To thismixture, HOBt (23.4 g, 174.6 mmol, 1.0 eq) and EDCI (40 g, 209.5 mol,1.2 eq) were added sequentially while keeping the reaction temperaturebetween −5° C. to 0° C. The resulting mixture was stirred at −5° C. for30 min. N,O-Dimethylhydroxylamine hydrochloride (19 g, 192.1 mmol, 1.1eq) was added in portions while keeping the reaction temperature between−5° C. to 0° C. After stirring at −5° C. for 30 min., the reactionmixture was allowed to warm to RT and stirred at RT for 16 h, and thenquenched with water (200 mL). The organic layer was separated, washedwith water (2×200 mL) and brine (150 mL), dried over anhydrous Na₂SO₄and filtered. The filtrate was concentrated in vacuo. The product wasslurried in PE (500 mL) and stirred at RT for 30 min. The solid wascollected by filtration and further dried in vacuo to afford tert-butyl2-(methoxy(methyl)amino)-2-oxoethylcarbamate (compound 237).

Compound 238 was prepared from 2-chloro-6-methylbenzoic acid inanalogous fashion to compound A-2 in Method A.

To a solution of compound 238 (40 g, 163 mmol, 1.0 eq) in THF (200 mL)at −30° C. under an argon atmosphere, a solution of n-butyllithium inTHF (2.5 M, 140 mL, 408 mmol, 2.5 eq) was added drowpwise over 30 minwhile keeping the inner temperature between −30° C. and −10° C. Theresulting mixture was stirred at −30° C. for an additional 30 min. To asolution of compound 237 (35 g, 198 mmol, 1.2 eq) in THF (200 mL) at−30° C. under an argon atmosphere, a solution of isopropylmagnesiumchloride in THF (2 M, 115 mL, 268 mmol. 1.65 eq) was added dropwise over30 min while keeping inner temperature between −30° C. and −10° C. Theresulting mixture was stirred at −30° C. for 30 min. This solution wasadded slowly to above reaction mixture while keeping the innertemperature between −30° C. and −10° C. The resulting mixture wasstirred at −15° C. for an additional 1 h. The reaction mixture wasquenched with water (50 mL) and then acidified with 6 N HCl (160 mL) at−10° C. to 0° C. to adjust the pH to 1-3. The mixture was allowed towarm to RT and concentrated in vacuo to afford compound 239. The residuewas dissolved in MeOH (400 mL), and then conc. HCl (200 mL) was addedquickly at RT. The resulting mixture was stirred at reflux for 1 h. Thereaction mixture was concentrated in vacuo to reduce the volume to about450 mL. The residue was extracted with about a 2:1 mixture of PE and EA(2×500 mL). The aqueous layer was basified with concentrated ammoniumhydroxide to adjust the pH to 9-10 while keeping the inner temperaturebetween −10° C. and 0° C. The mixture was extracted with DCM (3×100 mL),washed with brine, dried over Na₂SO₄ and filtered. The filtrate waspurified by flash column chromatography on silica gel (2-30% ethylacetate-petroleum ether) to afford compound 240.

Compound 241 was prepared from compound 240 and (E-2) using Method G.ESI-MS m/z: 403.2 [M+H]⁺.

Example 147

Compound 242 was prepared from compound 241 through coupling to2-methoxypyridin-4-ylboronic acid according to Method J. ESI-MS m/z:476.2 [M+H]⁺.

Example 148

Compound 243 was prepared from compound 1 through coupling with4-chloro-6-(trifluoromethyl)pyrimidin-2-amine according to Method G.ESI-MS m/z: 460.2 [M+H]⁺.

Example 149

Compound 245 was synthesized from compound B-4 according to Method Busing neopentylamine. Compound 246 was prepared from compound 245according to Method G using 2-amino-4-chloropyrimidine-5-carbonitrile.ESI-MS m/z: 411.2 [M+H]⁺.

Example 150

Compound 248 was synthesized from compound B-4 according to Method Busing thiazol-4-amine. Compound 249 was prepared from compound 248according to Method G using 2-amino-4-chloropyrimidine-5-carbonitrile.ESI-MS m/z: 424.1 [M+H]⁺.

Example 151

Compound 251 was synthesized from compound B-4 according to Method Busing p-toluidine. Compound 252 was prepared from compound 251 accordingto Method G using 2-amino-4-chloropyrimidine-5-carbonitrile. ESI-MS m/z:431.1 [M+H]⁺.

Example 152

Compound 254 was synthesized from compound B-4 according to Method Busing 2,4-difluoroaniline. Compound 255 was prepared from compound 254according to Method G using 2-amino-4-chloropyrimidine-5-carbonitrile.ESI-MS m/z: 453.1 [M+H]⁺.

Example 153

Compound 257 was synthesized from compound B-4 according to Method Busing 2,4,6-trifluoroaniline. Compound 258 was prepared from compound257 according to Method G using2-amino-4-chloropyrimidine-5-carbonitrile. ESI-MS m/z: 471.0 [M+H]⁺.

Example 154

Compound 260 was synthesized from compound B-4 according to Method Busing benzo[d][1,3]dioxol-5-amine. Compound 261 was prepared fromcompound 260 according to Method G using2-amino-4-chloropyrimidine-5-carbonitrile. ESI-MS m/z: 461.1 [M+H]⁺.

Example 155

Compound 263 was synthesized from compound B-4 according to Method Busing 2,5-difluoroaniline. Compound 264 was prepared from compound 263according to Method G using 2-amino-4-chloropyrimidine-5-carbonitrile.ESI-MS m/z: 453.1 [M+H]⁺.

Example 156

Compound 266 was synthesized from compound B-4 according to Method Busing 2-fluoroaniline. Compound 267 was prepared from compound 266according to Method G using 2-amino-4-chloropyrimidine-5-carbonitrile.ESI-MS m/z: 435.1 [M+H]⁺.

Example 157

Compound 269 was synthesized from compound B-4 according to Method Busing 3,4-difluoroaniline. Compound 270 was prepared from compound 269according to Method G using 2-amino-4-chloropyrimidine-5-carbonitrile.ESI-MS m/z: 453.0 [M+H]⁺.

Example 158

Compound 272 was synthesized from compound B-4 according to Method Busing 3,5-difluoroaniline. Compound 273 was prepared from compound 272according to Method G using 2-amino-4-chloropyrimidine-5-carbonitrile.ESI-MS m/z: 453.1 [M+H]⁺.

Example 159

Compound 276 was synthesized from compound B-4 according to Method Busing methylamine. Compound 276 was prepared from compound 275 accordingto Method G using 2-amino-4-chloropyrimidine-5-carbonitrile. ESI-MS m/z:355.1 [M+H]⁺.

Example 160

Compound 278 was synthesized from compound B-4 according to Method Busing 2,6-difluoroaniline. Compound 279 was prepared from compound 278according to Method G using 2-amino-4-chloropyrimidine-5-carbonitrile.ESI-MS m/z: 453.1 [M+H]⁺.

Example 161

Compound 281 was synthesized from compound B-4 according to Method Busing 2,3-difluoroaniline. Compound 282 was prepared from compound 281according to Method G using 2-amino-4-chloropyrimidine-5-carbonitrile.ESI-MS m/z: 453.1 [M+H]⁺.

Example 162

Compound 284 was synthesized from compound B-4 according to Method Busing 3-aminobenzonitrile. Compound 285 was prepared from compound 284according to Method G using 2-amino-4-chloropyrimidine-5-carbonitrile.ESI-MS m/z: 442.1 [M+H]⁺.

Example 163

Compound 287 was synthesized from compound B-4 according to Method Busing 3-methoxyaniline. Compound 288 was prepared from compound 287according to Method G using 2-amino-4-chloropyrimidine-5-carbonitrile.ESI-MS m/z: 447.1 [M+H]⁺.

Example 164

Compound 290 was synthesized from compound B-4 according to Method Busing 4-fluoro-3-methoxyaniline. Compound 291 was prepared from compound290 according to Method G using2-amino-4-chloropyrimidine-5-carbonitrile. ESI-MS m/z: 465.1 [M+H]⁺.

Example 165

Compound 293 was synthesized from compound B-4 according to Method Busing benzofuran-5-amine. Compound 294 was prepared from compound 293according to Method G using 2-amino-4-chloropyrimidine-5-carbonitrile.ESI-MS m/z: 457.1 [M+H]⁺.

Example 166

Compound 296 was synthesized from compound B-4 according to Method Busing cyclopentylamine. Compound 297 was prepared from compound 296according to Method G using 2-amino-4-chloropyrimidine-5-carbonitrile.ESI-MS m/z: 409.1 [M+H]⁺.

Example 167

Compound 299 was synthesized from compound B-4 according to Method Busing cyclohexylamine. Compound 300 was prepared from compound 299according to Method G using 2-amino-4-chloropyrimidine-5-carbonitrile.ESI-MS m/z: 423.2 [M+H]⁺.

Example 168

Compound 302 was synthesized from compound B-4 according to Method Busing benzylamine. Compound 303 was prepared from compound 301 accordingto Method G using 2-amino-4-chloropyrimidine-5-carbonitrile. ESI-MS m/z:431.1 [M+H]⁺.

Example 169

Compound 305 was synthesized from compound B-4 according to Method Busing pyridin-3-amine. Compound 306 was prepared from compound 305according to Method G using 2-amino-4-chloropyrimidine-5-carbonitrile.ESI-MS m/z: 418.1 [M+H]⁺.

Example 170

Compound 308 was synthesized from compound B-4 according to Method Busing ethylamine. Compound 309 was prepared from compound 308 accordingto Method G using 2-amino-4-chloropyrimidine-5-carbonitrile. ESI-MS m/z:369.1 [M+H]⁺.

Example 171

Compound 311 was synthesized from compound B-4 according to Method Busing isopropyl 3-aminobenzoate. Compound 312 was prepared from compound311 according to Method G using2-amino-4-chloropyrimidine-5-carbonitrile. ESI-MS m/z: 503.1 [M+H]⁺.

Example 172

Compound 312 (8 mg, 0.016 mmol) dissolved in MeOH (2 ml) was treatedwith LiOH (4 mg, 0.16 mmol) in 1 ml water. This mixture was stirred atroom temperature for 2 h. The solution was then directly purified byHPLC to give compound 313. ESI-MS m/z: 461.1 [M+H]⁺.

Example 173

Compound 315 was synthesized from compound B-4 according to Method Busing methyl 3-aminobenzoate. Compound 316 was prepared from compound315 according to Method G using2-amino-4-chloropyrimidine-5-carbonitrile. ESI-MS m/z: 475.1 [M+H]⁺.

Example 174

Compound 318 was synthesized from compound B-4 according to Method Busing quinolin-7-amine. Compound 319 was prepared from compound 318according to Method G using 2-amino-4-chloropyrimidine-5-carbonitrile.ESI-MS m/z: 467.1 [M+H]⁺.

Example 175

Compound 321 was synthesized from compound B-4 according to Method Busing. naphthalen-2-amine. Compound 322 was prepared from compound 321according to Method G using 2-amino-4-chloropyrimidine-5-carbonitrile.ESI-MS m/z: 468.1 [M+H]⁺.

Example 176

Compound 324 was synthesized from compound B-4 according to Method Busing isopropylamine. Compound 325 was prepared from compound 324according to Method G using 2-amino-4-chloropyrimidine-5-carbonitrile.Compound 326 was prepared from compound 325 according to Method J using1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one.ESI-MS m/z: 456.2 [M+H]⁺.

Example 177

Compound 325 was prepared according to Example 176. Compound 327 wasprepared from compound 325 according to Method J using2-methoxypyrimidin-5-ylboronic acid. ESI-MS m/z: 457.2 [M+H]⁺.

Example 178

Compound 325 was prepared according to Example 176. Compound 328 wasprepared from compound 325 according to Method J using2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.ESI-MS m/z: 457.2 [M+H]⁺.

Example 179

Compound 324 was prepared according to Example 176. Compound 329 wasprepared from compound 324 according to Method G using4-amino-6-chloropyrimidine-5-carbonitrile. ESI-MS m/z: 383.1 [M+H]⁺.

Example 180

Compound 331 was synthesized from compound B-4 according to Method Busing isoxazol-3-amine. Compound 332 was prepared from compound 321according to Method G using 2-amino-4-chloropyrimidine-5-carbonitrile.Compound 333 was prepared from compound 332 according to Method J using2-methoxypyrimidin-5-ylboronic acid. ESI-MS m/z: 482.2 [M+H]⁺.

Example 181

Compound 332 was prepared according to Example 180. Compound 334 wasprepared from compound 332 according to Method J using2-methylpyrimidin-5-ylboronic acid. ESI-MS m/z: 466.2 [M+H]⁺.

Example 182

Compound 331 was prepared according to Example 180. Compound 335 wasprepared from compound 331 according to Method G using4-amino-6-chloropyrimidine-5-carbonitrile. Compound 336 was preparedfrom compound 335 according to Method J using2-methylpyrimidin-5-ylboronic acid. ESI-MS m/z: 466.2 [M+H]⁺.

Example 183

Compound 331 was prepared according to Example 180. Compound 335 wasprepared from compound 331 according to Method G using4-amino-6-chloropyrimidine-5-carbonitrile. Compound 336 was preparedfrom compound 335 according to Method J using2-methoxypyrimidin-5-ylboronic acid. ESI-MS m/z: 482.1 [M+H]⁺.

Example 184

Compound 332 was prepared according to Example 180. Compound 338 wasprepared from compound 332 according to Method J using1-methyl-5-(4,4,5,5-tetramehyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one.ESI-MS m/z: 481.2 [M+H]⁺.

Example 185

To a solution of 2-chloro-6-methylbenzoicacid (339) (300 g, 1.76 mol,1.0 eq) and DMF (0.5 mL) in DCM (500 mL) at RT, oxalyl chloride (249 g,1.92 mol, 1.1 eq) was added slowly (over 5 min). The resulting mixturewas stirred at RT for 2 h and then concentrated in vacuo to afford2-chloro-6-methylbenzoyl chloride (340) which was used directly in thenext step.

To a solution of (4-methoxyphenyl)methanamine (264 g, 2.4 mol, 1.eq) inDCM (1800 mL), a solution of 2-chloro-6-methylbenzoyl chloride (340) inDCM (150 mL) was added dropwise while keeping the reaction temperaturebetween 25° C. to 40° C. The resulting mixture was stirred at RT for 2h, and then water (600 mL) was added. The organic layer was separated,washed with water (2×300 mL), dried over Na₂SO₄ and filtered. Thefiltrate was concentrated in vacuo and the residue was slurried inpetroleum ether (300 mL) and stirred at RT for 30 min. The solid wascollected by filtration and further dried in vacuo to affordN-(4-methoxybenzyl)-2-chloro-6-methylbenzamide (341).

To a solution of N-(4-methoxybenzyl)-2-chloro-6-methylbenzamide (341)(40 g, 138 mmol, 1.0 eq) in THF (200 mL) at −30° C. under an argonatmosphere, a solution of n-butyllithium in hexanes (2.5M, 139 mL, 346mmol, 2.5 eq) was added dropwise over 30 min while keeping the innertemperature between −30° C. and −10° C. The resulting mixture wasstirred at −30° C. for 30 min.

To a solution of (S)-tert-butyl1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (48 g, 165 mmol, 1.2eq) in THF (200 mL) at −30° C. under an argon atmosphere, a solution ofisopropylmagnesium chloride in THF (2 M, 115 mL, 207 mmol, 1.65 eq) wasadded dropwise over 30 min while keeping the inner temperature between−30° C. and −10° C. The resulting mixture was stirred at −30° C. for 30min. This solution was slowly added to the above reaction mixture whilekeeping the inner temperature between −30° C. and −10° C. The resultingmixture was stirred at −15° C. for 1 h. The reaction mixture wasquenched with water (50 mL) and then acidified with 6N HCl (160 mL) at−10° C.-0° C. to adjust the pH to 1-3. The mixture was allowed to warmto RT and concentrated in vacuo to afford (S)-tert-butyl4-(2-((4-methoxybenzyl)carbamoyl)-3-chlorophenyl)-3-oxobutan-2-ylcarbamate(342). The residue was dissolved in MeOH (400 mL), and then conc. HCl(200 mL) was added quickly at RT. The resulting mixture was stirred atreflux for 1 h. The reaction mixture was concentrated in vacuo to reducethe volume to about 450 mL. The residue was extracted with a mixture ofpetroleum ether and EtOAc (2:1, v/v, 2×500 mL), and then separated. Theaqueous layer was basified with concentrated ammonium hydroxide toadjust the pH to 9-10 while keeping the inner temperature between −10°C. and 0° C. The mixture was extracted with DCM (3×100 mL), washed withbrine, dried over Na₂SO₄ and filtered. The filtrate was concentrated invacuo and the residue was dissolved in MeOH (600 mL) at RT.D-(−)-Tartaric acid (17 g, 110.4 mmol, 0.8 eq) was added in one portionat RT. The resulting mixture was stirred at RT for 10 h. The solid wascollected by filtration and washed with ethyl acetate (3×50 mL). Thesolid was suspended in water (300 mL) and neutralized with concentratedammonium hydroxide to adjust the pH to 9-10 at RT. The mixture wasextracted with DCM (3×100 mL). The organic layer was washed with brine,dried over Na₂SO₄, and filtered. The filtrate was concentrated in vacuoto afford(S)-2-(4-methoxybenzyl)-3-(1-aminoethyl)-8-chloroisoquinolin-1(2H)-one(343).

To a solution of(S)-2-(4-methoxybenzyl)-3-(1-aminoethyl)-8-chloroisoquinolin-1(2H)-one(343) (20 g, 58.3 mmol, 1.0 eq) and NaHCO₃ (12.7 g, 291.51 mmol, 5.0 eq)in DCM (120 mL) and water (60 mL) at RT, Fmoc-Cl (15.7 g, 61.22 mmol,1.05 eq) was slowly added and the resulting mixture was stirred at RTfor 1 h. The reaction mixture was poured into water (200 mL) andextracted with DCM (3×100 mL). The combined organic layers were washedwith brine, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo to afford (S)-(9H-fluoren-9-yl)methyl1-(2-(4-methoxybenzyl)-8-chloro-1-oxo-1,2-dihydroisoquinolin-3-yl)ethylcarbamate(344).

(S)-(9H-fluoren-9-yl)methyl1-(8-chloro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)ethylcarbamate(344) (80 g, 142 mmol, 1.0 eq) was dissolved in 2,2,2-trifluoroaceticacid (300 mL) and the resulting mixture was stirred at reflux for 2 h.The mixture was allowed to cool to RT and then concentrated in vacuo.The residue was poured into water and then neutralized with NH₃*H₂O toadjust the pH value to 6-7 under 0° C. The resulting mixture was stirredat RT for 30 min. The solid was collected by filtration, rinsed withwater (2×50 mL) and dried in vacuo to afford (S)-(9H-fluoren-9-yl)methyl1-(8-chloro-1-oxo-1,2-dihydroisoquinolin-3-yl)ethylcarbamate (345).

To a solution of(S)-(9H-fluoren-9-yl)methyl1-(8-chloro-1-oxo-1,2-dihydroisoquinolin-3-yl)ethylcarbamate(345) (58 g, 130 mmol, 1.0 eq) and DMF (0.5 mL) in toluene (300 mL),sulfurous dichloride (78 g, 0.65 mol, 5.0 eq) was added slowly, and theresulting mixture was stirred at reflux for 2.5 h. The mixture wasallowed to cool to RT and then concentrated in vacuo. The residue waspoured into water (200 mL) and extracted with ethyl acetate (3×100 mL).The organic layer was washed with water (2×100 mL) and brine (100 mL),dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentratedin vacuo and the residue was purified by flash column chromatography onsilica gel (5-20% ethyl acetate-petroleum ether) to afford(S)-(9H-fluoren-9-yl)methyl1-(1,8-dichloroisoquinolin-3-yl)ethylcarbamate (346).

To a solution of(S)-(9H-fluoren-9-yl)methyl-1-(1,8-dichloroisoquinolin-3-yl)ethylcarbamate(346) (36 g, 77.7 mmol, 1.0 eq) in THF (300 mL) under argon,tributyl(vinyl)stannane (27 g, 85.5 mmol, 1.1 eq), Pd(OAc)₂ (5.23 g,23.3 mmol, 0.3 eq) and PPh₃ (12.2 g, 46.6 mmol, 0.6 eq) were added, andthe resulting mixture was stirred at reflux for 16 h. The mixture wasallowed to cool to RT and then concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (2-30% ethylacetate-petroleum ether) to afford (S)-(9H-fluoren-9-yl)methyl1-(8-chloro-1-vinylisoquinolin-3-yl)ethylcarbamate (347).

To a suspension of (S)-(9H-fluoren-9-yl)methyl1-(8-chloro-1-vinylisoquinolin-3-yl)ethylcarbamate (347) (10.6 g, 23.3mmol, 1.0 eq) in 1,4-dioxane (200 mL) and water (100 mL), OsO₄ (50 mg)was added and the resulting mixture was stirred at RT for 30 min. Tothis mixture, NaIO₄ (15 g, 69.9 mmol, 3.0 eq) was added, and then themixture was stirred at RT for 16 h. The mixture reaction was poured intowater (200 mL) and extracted with ethyl acetate (3×100 mL). The organiclayer was washed with water (2×100 mL) and brine (100 mL), dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo.The residue was purified by flash column chromatography on silica gel(5-20% ethyl acetate-petro ether) to afford (S)-(9H-fluoren-9-yl)methyl1-(8-chloro-1-formylisoquinolin-3-yl)ethylcarbamate (348).

To a solution of (S)-(9H-fluoren-9-yl)methyl1-(8-chloro-1-formylisoquinolin-3-yl)ethylcarbamate (348) (12.0 g, 26.3mmol, 1.0 eq) in DMF (150 mL), OXONE (30 g, 48.78 mmol, 1.85 eq) wasadded and the resulting mixture was stirred at RT over night. Themixture was poured into water (600 mL) and then filtered. The solid wasdissolved in ethyl acetate (100 mL), and then PE (300 mL) was addeddropwise to this solution. The precipitate was collected by filtrationto afford(S)-3-(1-(((9H-fluoren-9-yl)methoxy)carbonylamino)ethyl)-8-chloroisoquinoline-1-carboxylicacid (349).

To a solution of(S)-3-(1-(((9H-fluoren-9-yl)methoxy)carbonylamino)ethyl)-8-chloroisoquinoline-1-carboxylicacid (349) (25.5 g, 54.0 mmol, 1.0 eq) and DMF (1.5 mL, 19.3 mmol, 0.35eq) in CH₂Cl₂ (200 mL), oxalyl chloride (30 mL, 177.7 mmol, 3.29 eq) wasadded dropwise slowly. The resulting mixture was stirred at RT for 1 h.The reaction mixture was concentrated in vacuo and the residue wasdissolved in CH₂Cl₂ (100 mL). This solution was added dropwise to asolution of tetrahydro-2H-pyran-4-amine (15 mL, 133 mmol, 2.46 eq) andEt₃N (30 mL, 210.9 mmol, 3.90 eq) in CH₂Cl₂ (200 mL) at 0° C. Themixture was warmed to RT and stirred for 30 min. 5% Hydrochloric acidaqueous solution was added to the reaction mixture until the pH=1˜2. Themixture was poured into water (400 mL), extracted with CH₂Cl₂ (150mL×2). The organic layer was dried over anhydrous Na₂SO₄ and filtered.The filtrate was concentrated in vacuo. The residue was purified byflash column chromatography on silica gel (5-10% MeOH-DCM) to afford(S)-(9H-fluoren-9-yl)methyl1-(8-chloro-1-(tetrahydro-2H-pyran-4-ylcarbamoyl)isoquinolin-3-yl)ethylcarbamate(351).

(S)-(9H-fluoren-9-yl)methyl1-(8-chloro-1-(tetrahydro-2H-pyran-4-ylcarbamoyl)isoquinolin-3-yl)ethylcarbamate(351) (20.0 g, 36.0 mmol, 1.0 eq) was suspended in morpholine (200 mL),and then stirred at 40-50° C. for 1 h. The reaction mixture wasconcentrated in vacuo and then 1,4-dioxane (200 mL) was added to theresidue. The mixture was concentrated in vacuo. The operation wasrepeated for 3-4 times. The residue was purified by flash columnchromatography on silica gel (2-10% MeOH-DCM) to afford(S)-3-(1-aminoethyl)-8-chloro-N-(tetrahydro-2H-pyran-4-yl)isoquinoline-1-carboxamide(352).

The amine 352 was coupled to 4-amino-6-chloropyrimidine-5-carbonitrilein the SnAr according to Method G to give compound 353. ESI-MS m/z:452.2 [M+H]⁺.

Example 186

The amine 352 was prepared according to Example 185. Compound 352 wascoupled to 4-amino-6-chloropyrimidine-5-carbonitrile according to MethodG to give compound 354. ESI-MS m/z: 452.2 [M+H]⁺.

Example 187

Compound 355 was prepared from compound 1 according to Method G using4-amino-6-chloropyrimidine-5-carbonitrile. Compound 356 was preparedfrom compound 355 according to Method J using2-methoxy-pyrimidin-5-ylboronic acid. ESI-MS m/z: 491.2 [M+H]⁺.

Example 188

To benzoic acid B-1 (10.00 g, 58.6 mmol) was added dichloromethane (63ml) and DMF (0.227 ml, 2.93 mmol). Thionyl chloride (4.24 ml, 58.0 mmol)was added over 10 min, and the resulting mixture was stirred for 2 h.The reaction was cooled to 0-5° C. and i-PrNH₂ (15.73 ml, 185 mmol) wasslowly added. The resulting mixture was stirred at room temperature for0.5 h. The mixture was diluted with dichloromethane (63 ml) and water.The phases were separated and the organic layer was concentrated. Theproduct was precipitated by addition of heptane to give the amide 357.

The amide 357 (50.0 g, 236 mmol) and THF (250 mL) were charged in aflask equipped with magnetic stirrer and thermocouple. The mixture wascooled to 0-5° C. and a solution of 2.3M hexyllithium in hexanes (232ml, 534 mmol) was added. The mixture was stirred for 15 min. In aseparate flask, a cooled solution (S)-benzyl1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (85 g, 319 mmol) inTHF (500 mL) was treated with i-PrMgCl (168 ml, 338 mmol). After 15 min,the latter solution was cannulated into the former over 30 min. Thereaction was stirred for 1 h at room temperature. The mixture wascannulated into a cooled solution (0-5° C.) of isobutyric acid (94 ml,1032 mmol) in MTBE (625 mL). The mixture was warmed to room temperatureand 3% brine (650 mL) was added. The phases were separated and theorganic layer washed with water (650 mL). The organic layer was driedwith Na₂SO₄ and concentrated until solid formed. The product wasfiltered to give the ketone 358.

A mixture of the ketone 358 (25.00 g, 60.0 mmol) in i-PrOAc (450 mL) wastreated with H₂SO₄ (15.98 ml, 300 mmol) and heated to 70° C. After 1 h,the reaction was cooled to 50° C. and H₂SO₄ (38.4 ml, 720 mmol) wasadded. The resulting mixture was stirred at 70° C. for 5 h. Aftercooling to room temperature, NH₄OH (284 ml, 2039 mmol) was added. Theorganic phase was separated and the aqueous layer was extracted withi-PrOAc (100 mL). The combined organic layers were dried over Na₂SO₄,filtered and concentrated. The resulting amine 324 was used directly inthe next step.

A solution of the amine 324 (15.00 g, 56.7 mmol) in n-BuOH (225 mL) andHunig's base (19.79 ml, 113 mmol) was treated with4-amino-6-chloropyrimidine-5-carbonitrile (8.76 g, 56.7 mmol). Themixture was stirred at reflux for 5 h, then cooled to room temperature.The solid was filtered to give product 329.

A mixture of compound 329 (10.40 g, 27.2 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(9.58 g, 40.7 mmol), sodium carbonate (5.76 g, 54.3 mmol) andPdCl₂(Amphos)₂ (0.962 g, 1.358 mmol)) in dioxane/water (4:1, 208 mL))was heated to reflux for 4 h. The mixture was cooled to room temperatureand water (200 mL) was added. The solid was filtered, washed with water,and dried overnight. The solid was purified by column chromatographyeluting with 0-10% MeOH/dichloromethane to give compound 359. ESI-MSm/z: 456.2 [M+H]⁺.

Example 189

Compound 135 was prepared according to Example 87. Compound 360 wasprepared according to Example 88 using 4-(tributylstannyl)thiazole.ESI-MS m/z: 475.1 [M+H]⁺.

Example 190

Compound 135 was prepared according to Example 87. Compound 361 wasprepared according to Example 88 using 5-(tributylstannyl)thiazole.ESI-MS m/z: 475.1 [M+H]⁺.

Example 191

Compound 362 was prepared from compound 1 and2-methoxypyridin-4-ylboronic acid in analogous fashion to Example 2.Compound 363 was prepared as follows:2-amino-4-chloro-6-methylpyrimidine (5.00 g, 34.8 mmol) was suspended inACN (50 mL) and MeOH (70 mL). The mixture was charged with NIS (11.75 g,52.2 mmol) at room temperature and the mixture was heated to 60° C. for5 h. The mixture was cooled to room temperature and 80% of the volatileswere removed. The suspension was diluted with Et₂O (100 mL) and thesolids were filtered to obtain 10 g of4-chloro-5-iodo-6-methylpyrimidin-2-amine. A solution of iodide (500 mg,1.855 mmol) in DMF (40 mL) was charged with CuCN (332 mg, 3.71 mmol),Pd(PPh₃)₄(1072 mg, 0.928 mmol) and CuI (247 mg, 1.299 mmol). The mixturewas degassed for 10 min, then heated to 80° C. for 90 min. The mixturewas cooled to room temperature and the material was partitioned betweenwater and EA, then filtered on celite. The organic layer of the filtratewas washed several times with brine, dried and concentrated. Thefiltrate was pre-adsorbed on SiO₂ and purified on ISCO 40 g (EA/hex) togive 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile 363. Compound363 was coupled to compound 362 according to Method G to afford compound364. ESI-MS m/z: 504.3 [M+H]⁺.

Example 192

Compound 135 was prepared according to Example 87. Compound 365 wasprepared according to Example 88 using 2-(tributylstannyl)oxazole.ESI-MS m/z: 459.1 [M+H]⁺.

Example 193

Compound 135 was prepared according to Example 87. Compound 366 wasprepared according to Example 88 using4,5-dimethyl-2-(tributylstannyl)thiazole. ESI-MS m/z: 503.2 [M+H]⁺.

Example 194

Compound 135 was prepared according to Example 87. Compound 367 wasprepared according to Example 88 using tributyl(thiophen-2-yl)stannane.ESI-MS m/z: 474.1 [M+H]⁺.

Example 195

Compound 135 was prepared according to Example 87. Compound 368 wasprepared according to Example 88 using5-methyl-2-(tributylstannyl)thiazole. ESI-MS m/z: 489.1 [M+H]⁺.

Example 196

Compound 135 was prepared according to Example 87. Compound 369 wasprepared according to Example 88 using2-ethoxy-4-(tributylstannyl)thiazole. ESI-MS m/z: 519.1 [M+H]⁺.

Example 197

Compound 135 was prepared according to Example 87. Compound 370 wasprepared according to Example 88 using2-(methylsulfonyl)-4-(tributylstannyl)thiazole. ESI-MS m/z: 553.1[M+H]⁺.

Example 198

Compound 135 was prepared according to Example 87. Compound 371 wasprepared according to Example 88 using2-ethoxy-5-(tributylstannyl)thiazole. ESI-MS m/z: 519.2 [M+H]⁺.

Example 199

Compound 135 was prepared according to Example 87. Compound 372 wasprepared according to Example 88 using2-methyl-5-(tributylstannyl)thiazole. ESI-MS m/z: 489.1 [M+H]⁺.

Example 200

Compound 135 was prepared according to Example 87. Compound 373 wasprepared according to Example 99 using thiophen-3-ylboronic acid. ESI-MSm/z: 489.1 [M+H]⁺.

Example 201

Compound 135 was prepared according to Example 87. Compound 374 wasprepared according to Example 88 using2-(methylthio)-5-(tributylstannyl)thiazole. ESI-MS m/z: 521.1 [M+H]⁺.

Example 202

Compound 135 was prepared according to Example 87. Compound 375 wasprepared according to Example 88 using 2-(tributylstannyl)pyridine.ESI-MS m/z: 521.1 [M+H]⁺.

Example 203

Compound 135 was prepared according to Example 87. Compound 376 wasprepared according to Example 99 using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleinstead of 3-(piperidin-1-ylsulfonyl)phenylboronic acid. ESI-MS m/z:472.2 [M+H]⁺.

Example 204

Compound 135 was prepared according to Example 87. Compound 377 wasprepared according to Example 99 using1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleinstead of 3-(piperidin-1-ylsulfonyl)phenylboronic acid. Benzylatedintermediate 377 (51 mg, 0.093 mmol) was dissolved in 8 mL of(EtOAc/MeOH, 5:3) and 150 μL of 6N HCl and placed under 1 atmosphere ofhydrogen in presence of Pd/C (10%) for 4 h. After removal of thecatalyst by filtration, the volatiles were removed and compound purifiedby HPLC to give the pyrazole 378. ESI-MS m/z: 458.2 [M+H]⁺.

Example 205

Compound 135 was prepared according to Example 87. Compound 379 wasprepared according to Example 99 using furan-3-ylboronic acid. ESI-MSm/z: 458.1 [M+H]⁺.

Example 207

Compound 135 was prepared according to Example 87. Compound 381 wasprepared according to Example 99 using 4-methylthiophen-2-ylboronicacid. ESI-MS m/z: 488.1 [M+H]⁺.

Example 208

Compound 135 was prepared according to Example 87. Compound 382 wasprepared according to Example 88 using2-methoxy-5-(tributylstannyl)thiazole. ESI-MS m/z: 505.1 [M+H]⁺.

Example 209

Compound 135 was prepared according to Example 87. Compound 383 wasprepared according to Example 99 using 6-methoxypyridin-3-ylboronicacid. ESI-MS m/z: 499.1 [M+H]⁺.

Example 210

Compound 135 was prepared according to Example 87. Compound 384 wasprepared according to Example 99 using 6-methylpyridin-3-ylboronic acid.ESI-MS m/z: 483.1 [M+H]⁺.

Example 211

Compound 135 was prepared according to Example 87. Compound 385 wasprepared according to Example 88 using2-methyl-4-(tributylstannyl)thiazole. ESI-MS m/z: 489.1 [M+H]⁺.

Example 212

Compound 135 was prepared according to Example 87. Compound 386 wasprepared from compound 135 according to Example 88 using5-(tributylstannyl)thiazole. Compound 387 was prepared from compound 386in analogous fashion to Example 89 using1-methyl-6-oxo-1,6-dihydropyridin-3-ylboronic acid. ESI-MS m/z: 548.3[M+H]⁺.

Example 213

Compound 135 was prepared according to Example 87. Compound 388 wasprepared from compound 135 according to Example 88 using5-(tributylstannyl)thiazole. Compound 387 was prepared from compound 386in analogous fashion to Example 89 using 2-methoxypyrimidin-5-ylboronicacid. ESI-MS m/z: 549.2 [M+H]⁺.

Example 214

Compound 135 was prepared according to Example 87. Compound 390 wasprepared from compound 135 according to Example 88 using2-methoxy-4-(tributylstannyl)thiazole. Compound 391 was prepared fromcompound 390 in analogous fashion to Example 89 using1-methyl-6-oxo-1,6-dihydropyridin-3-ylboronic acid. ESI-MS m/z: 578.3[M+H]⁺.

Example 215

Compound 135 was prepared according to Example 87. Compound 392 wasprepared from compound 135 according to Example 88 using4-(tributylstannyl)thiazole. Compound 393 was prepared from compound 392in analogous fashion to Example 89 using1-methyl-6-oxo-1,6-dihydropyridin-3-ylboronic acid. ESI-MS m/z: 548.2[M+H]⁺.

Example 216

Compound 135 was prepared according to Example 87. Compound 394 wasprepared according to Example 88 using tributyl(1-ethoxyvinyl)stannane.ESI-MS m/z: 434.1 [M+H]⁺.

Example 217

Compound 135 was prepared according to Example 87. Compound 395 wasprepared from compound 135 according to Example 88 using2-ethoxy-4-(tributylstannyl)thiazole. Compound 396 was prepared fromcompound 395 in analogous fashion to Example 89 using2-methoxypyrimidin-5-ylboronic acid. ESI-MS m/z: 593.3 [M+H]⁺.

Example 218

Compound 135 was prepared according to Example 87. Compound 397 wasprepared according to Example 99 using 3-(methylsulfonyl)phenylboronicacid. ESI-MS m/z: 546.1 [M+H]⁺.

Example 219

Compound 135 was prepared according to Example 87. Compound 398 wasprepared according to Example 99 using 4-(methylsulfonyl)phenylboronicacid. ESI-MS m/z: 546.1 [M+H]⁺.

Example 220

Compound 135 was prepared according to Example 87. Compound 399 wasprepared according to Example 99 using3-(methylsulfonamido)phenylboronic acid. ESI-MS m/z: 561.1 [M+H]⁺.

Example 221

Compound 135 was prepared according to Example 87. Compound 400 wasprepared according to Example 99 using4-(methylsulfonamido)phenylboronic acid. ESI-MS m/z: 561.1 [M+H]⁺.

Example 222

Compound 135 was prepared according to Example 87. Compound 401 wasprepared according to Example 99 using5-(methylsulfonyl)pyridin-3-ylboronic acid. ESI-MS m/z: 547.1 [M+H]⁺.

Example 223

Compound 135 was prepared according to Example 87. Compound 402 wasprepared according to Example 99 using6-(methylsulfonyl)pyridin-3-ylboronic acid. ESI-MS m/z: 547.1 [M+H]⁺.

Example 224

Compound 135 was prepared according to Example 87. Compound 403 wasprepared according to Example 88 using2-(methylsulfonyl)-5-(tributylstannyl)thiazole. ESI-MS m/z: 553.1[M+H]⁺.

Example 225

Compound 135 was prepared according to Example 87. Compound 404 wasprepared according to Example 99 using 3-acetamidophenylboronic acid.ESI-MS m/z: 525.2 [M+H]⁺.

Example 226

Compound 135 was prepared according to Example 87. Compound 405 wasprepared according to Example 99 using 3-formylphenylboronic acid.ESI-MS m/z: 496.1 [M+H]⁺.

Example 227

Compound 135 was prepared according to Example 87. Compound 406 wasprepared according to Example 99 using 3-methoxyphenylboronic acid.ESI-MS m/z: 498.2 [M+H]⁺.

Example 228

Compound 135 was prepared according to Example 87. Compound 407 wasprepared according to Example 88 using2-(tributylstannyl)benzo[d]thiazole. ESI-MS m/z: 525.2 [M+H]⁺.

Example 229

Compound 135 was prepared according to Example 87. Compound 408 wasprepared according to Example 99 usingN-methyl-N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamideinstead of 3-(piperidin-1-ylsulfonyl)phenylboronic acid. ESI-MS m/z:575.2 [M+H]⁺.

Example 230

Compound 135 was prepared according to Example 87. Compound 409 wasprepared according to Example 99 using 3-acetylphenylboronic acid.ESI-MS m/z: 510.2 [M+H]⁺.

Example 231

Compound 135 was prepared according to Example 87. Compound 410 wasprepared according to Example 99 using3-(N,N-dimethylsulfamoylamino)phenylboronic acid. ESI-MS m/z: 581.3[M+H]⁺.

Example 232

A mixture of bromide 411 (500 mg, 1.893 mmol), bis(pinacolato)diboron(577 mg, 2.272 mmol) and KOAc (557 mg, 5.68 mmol) in DMSO (6 mL) wasbubbled with Ar for 10 min. The mixture was charged withPd(dppf)₂Cl₂-DCM complex (155 mg, 0.189 mmol) and heated to 85° C.overnight. The reaction was cooled to room temperature and diluted withEtOAc. The organic layer was washed with water, dried over Na₂SO₄,filtered, and pre-adsorbed on SiO₂. The residue was purified on SiO₂(20-40% EA/hex) to obtain the boronate ester. Compound 412 was preparedfrom the boronate ester and compound 135 according to Example 99. ESI-MSm/z: 575.2 [M+H]⁺.

Example 233

Compound 135 was prepared according to Example 87. Compound 413 wasprepared according to Example 99 using3-(N,N-dimethylsulfamoyl)phenylboronic acid. ESI-MS m/z: 575.2 [M+H]⁺.

Example 234

Compound 135 was prepared according to Example 87. Compound 414 wasprepared according to Example 99 using 3-sulfamoylphenylboronic acid.ESI-MS m/z: 547.2 [M+H]⁺.

Example 235

Compound 135 was prepared according to Example 87. Compound 415 wasprepared according to Example 99 usingN-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethenesulfonamideinstead of 3-(piperidin-1-ylsulfonyl)phenylboronic acid. ESI-MS m/z:573.3 [M+H]⁺.

Example 236

Compound 135 was prepared according to Example 87. Compound 416 wasprepared according to Example 99 using2-(3-(ethylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of 3-(piperidin-1-ylsulfonyl)phenylboronic acid. ESI-MS m/z:560.2 [M+H]⁺.

Example 237

Compound 135 was prepared according to Example 87. Compound 417 wasprepared according to Example 99 using2-(3-(cyclopropylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of 3-(piperidin-1-ylsulfonyl)phenylboronic acid. ESI-MS m/z:572.2 [M+H]⁺.

Example 238

Compound 135 was prepared according to Example 87. Compound 418 wasprepared according to Example 99 using3-(N-methylsulfamoyl)phenylboronic acid. ESI-MS m/z: 561.2 [M+H]⁺.

Example 239

Compound 135 was prepared according to Example 87. Compound 419 wasprepared according to Example 99 using3-(pyrrolidin-1-ylsulfonyl)phenylboronic acid. ESI-MS m/z: 601.2 [M+H]⁺.

Example 240

Compound 135 was prepared according to Example 87. Compound 420 wasprepared according to Example 99 using 3-(methylsulfonyl)phenylboronicacid. ESI-MS m/z: 561.2 [M+H]⁺.

Example 241

The amine 1 (4.00 g, 13.39 mmol) and 5-bromo-4-chloropyrimidine weresuspended in 1-butanol (65 mL) and charged with Hunig's Base (2.338 ml,13.39 mmol). The mixture was heated to reflux for 2 h. The reaction wascooled to room temperature, diluted with toluene (50 mL) andconcentrated. The residue was suspended in toluene (50 mL) and heated toreflux until all solids dissolved to form a solution. The solution wasthen cooled to 0° C. The resulting solid was filtered and washed withcold toluene to give the bromide 421.

Bromide 421 (104 mg, 0.189 mmol) and boronic acid (65.1 mg, 0.284 mmol)were dissolved in dioxane (2 mL) and Na₂CO₃ aq. (253 μl, 0.379 mmol).The mixture was bubbled with Ar for 5 min then charged with Pd(Ph₃P)₄(10.94 mg, 9.47 μmol). The mixture was heated to 90° C. for 3 h. Thereaction was cooled to room temperature, and poured into saturatedbicarbonate/EtOAc mixture. The phases were split and the organic layerwas dried, filtered and pre-adsorbed on SiO₂ (1.5 g). The residue waspurified on SiO₂ (12 g) (0-90 Acetone/DCM) to give the sulfonamide 422.ESI-MS m/z: 460.2 [M+H]⁺.

Example 242

Compound 8 (284 mg, 0.681 mmol) was dissolved in THF (15 mL) and treatedwith DMAP (20.80 mg, 0.170 mmol) and Boc₂O (1189 mg, 5.45 mmol). Themixture was stirred for 2 h at reflux and further Boc₂O (4 eq) wasadded. The reaction was cooled and the product was extracted with EtOAc.The organic layer was washed with sodium bicarbonate and brine. Theorganic layers were dried on Na₂SO₄, filtered, then pre-absorbed onsilica gel (2 g). The product was added to a silica gel (25 g) columnand was eluted with EtOAc (5 to 50%)/Hexanes to give compound 423.

In a flame dry flask, compound 423 (120 mg, 0.167 mmol) was dissolved incooled (0° C.) THF (5 mL). Isopropylmagnesium bromide in 2-MeTHF (0.115ml, 0.335 mmol) was added dropwise, and the mixture was stirred toreflux overnight. The reaction was cooled down and treated with 2 M HCl(0.418 ml, 0.837 mmol) for 4 h. The product was extracted with DCM,which was washed with sodium bicarbonate. The organic layers were driedon Na₂SO₄, filtered and concentrated. The product was dissolved in DCM(5 mL) and treated with TFA (0.064 ml, 0.837 mmol) at room temperatureovernight. The solvent was removed and the material was purified by HPLCto give the isopropyl ketone 424. ESI-MS m/z: 461.1 [M+H]⁺.

Example 243

Compound 423 was prepared according to Example 422. Compound 423 (125mg, 0.174 mmol) was dissolved in cooled (0° C.) THF (5 mL).Cyclopropylmagnesium bromide (0.5 M; 0.115 ml, 0.335 mmol) was addeddropwise and the mixture was stirred to reflux overnight. The reactionwas cooled and treated with conc. HCl 0.418 ml, 0.837 mmol) for 4 h. Theproduct was extracted with DCM, which was washed with sodiumbicarbonate. The organic layers were dried on Na₂SO₄, filtered andconcentrated. The product was dissolved in DCM (5 mL) and treated withTFA (3 mL) at room temperature overnight. The solvent was removed andthe compound was purified by HPLC to give the cyclopropyl ketone 425.ESI-MS m/z: 459.1 [M+H]⁺.

Example 244

(S)-3-(1-aminoethyl)-1-8-(trifluoromethyl)isoquinolin-1(2H)-one 427,made according to Method C, was coupled to5-bromo-4-chloropyrimidin-2-amine using Method G. Compound 428 wasprepared from compound 427 according to Example 99 using(3-(methylsulfonyl)phenyl)boronic acid. ESI-MS m/z: 580.1 [M+H]⁺.

Example 245

Compound 1 was prepared using 4,6-dichloronicotinonitrile according toMethod G to provide compound 429. To a mixture of isoquinolinone 432(0.23 mmol) and 1,4-dioxane (10 mL) was added ammonium hydroxidesolution (10 mL) and the mixture was placed in a 110° C. bath overnight.The reaction mixture was cooled and diluted with 2 volumes of brineafter which a solid is formed. Collection via vacuum filtration providedamide 430. ESI-MS m/z: 453.17 [M+H]⁺.

Example 246

To a mixture of isoquinolinone 430 (0.14 mmol) and 1,4-dioxane (4 mL)was added ammonium hydroxide solution (30%, 5 mL). The mixture wasplaced in a 150° C. bath for 3 days. The mixture was then recharged with5 mL of ammonium hydroxide (30%, 5 mL) and heated for an additional 24 hat 170° C. The reaction mixture was then added to excess methylenechloride and the layers were separated. The organic layer was washedwith brine (1×) and water (1×), dried over Na₂SO₄ and concentrated toprovide compound 431. ESI-MS m/z: 434.18 [M+H]⁺.

Example 247

Compound 432 was prepared from compound 111 in analogous fashion tocompound 112 in Example 73 except that difluoroazetidine hydrochloridewas used in place of dimethylamine. ESI-MS m/z: 584.2 [M+H]⁺.

Example 248

Compound 117 was prepared from compound 53 according to Example 78.Compound 433 was prepared from compound 117 according to Example 96.ESI-MS m/z: 475.0 [M+H]⁺.

Example 249

Compound 434 was prepared from compound 117 according to Example 249using 2,2-difluoroazetidine hydrochloride. ESI-MS m/z: 511.1 [M+H]⁺.

Example 250

Compound 1 was coupled to 4,6-dichloropyrimidin-2-amine according toMethod G to afford compound 435. ESI-MS m/z: 426.0 [M+H]⁺.

Example 251

Compound 135 was prepared according to Example 87. Compound 436 wasprepared according to Example 99 using 4-hydroxyphenylboronic acidinstead of 3-(piperidin-1-ylsulfonyl)phenylboronic acid. ESI-MS m/z:484.2 [M+H]⁺.

Example 252

Compound 440 was prepared from compound 1 using4-chloro-6-isopropoxypyrimidin-2-amine according to Method G. ESI-MSm/z: 450.1 [M+H]⁺.

Example 253

Compound 438 was prepared from compound 1 in analogous fashion tocompound 325 in Example 176 using4-amino-6-chloropyrimidine-5-carbonitrile. ESI-MS m/z: 450.1 [M+H]⁺.

Example 254

Compound 439 was prepared from compound 438 according to Example 176using 2-methoxy-pyrimidin-5-ylboronic acid in the coupling according toMethod J. ESI-MS m/z: 490.2 [M+H]⁺.

Example 255

Following Example 59, amine 103 was prepared from commercially available2-chloro-6-methylbenzoic acid according to Method A. Compound 103 wasthen coupled to 2-amino-4-chloropyrimidine-5-carbonitrile (E-2)according to Method G to afford compound 104. Compound 440 was preparedfrom compound 104 using 4-(tributylstannyl)pyridazine according tomethod I. ESI-MS m/z: 425.2 [M+H]⁺.

Example 256

Compound 441 was prepared from compound 111 according to Example 73,where cyclopropylamine was used instead of dimethylamine. ESI-MS m/z:545.8 [M+H]⁺.

Example 257

Compound 442 was prepared from compound 111 according to Example 73,where N,O-dimethylhydroxylamine was used instead of dimethylamine.ESI-MS m/z: 552.1 [M+H]⁺.

Example 258

Compound 443 was prepared from compound 8 usingN-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methanesulfonamideaccording to Method J. ESI-MS m/z: 553.3 [M+H]⁺.

TABLE 4 In Vitro IC₅₀ data for selected compounds. Greater than 1 uMIC50 (nM) Greater than 10 uM to 10 uM 1 uM to 100 nM Less than 100 nMPI3K δ 92, 111, 171, 173, 77, 82, 85, 104, 114, 75, 78, 122, 128, 5, 8,9, 10, 11, 12, 243 119, 148, 154, 155, 132, 133, 157, 168, 13, 15, 16,18, 20, 175, 182, 191, 211, 179, 204, 210, 214, 22, 23, 24, 25, 26, 220,228, 270, 279, 246, 258, 261, 273, 27, 28, 30, 31, 32, 291, 338, 354,401, 276, 288, 312, 316, 33, 34, 35, 36, 37, 402, 425, 429, 433, 333,335, 336, 337, 38, 39, 40, 41, 42, 434, 441 353, 366, 368, 375, 43, 44,45, 46, 47, 376, 378, 379, 383, 48, 49, 50, 51, 52, 397, 408, 414, 416,53, 55, 57, 59, 60, 418, 422, 424, 428, 61, 62, 63, 65, 66, 430, 432,435, 436, 68, 70, 72, 74, 76, 442 89, 91, 94, 96, 98, 100, 102, 105,106, 107, 108, 112, 113, 115, 116, 124, 125, 126, 127, 129, 130, 136,138, 140, 145, 151, 152, 153, 156, 159, 161, 163, 164, 165, 166, 167,169, 177, 181, 183, 185, 187, 189, 192, 193, 196, 199, 203, 205, 206,207, 217, 222, 223, 224, 226, 230, 231, 232, 233, 234, 235, 241, 242,249, 252, 255, 264, 267, 282, 285, 297, 300, 303, 306, 309, 325, 326,327, 328, 329, 332, 334, 356, 359, 360, 361, 364, 365, 367, 369, 370,371, 372, 373, 374, 380, 382, 387, 389, 391, 393, 394, 396, 399, 403,410, 412, 413, 415, 417, 419, 431, 440, 443 PI3K γ□ 92, 111, 128, 171,75, 77, 78, 114, 119, 12, 30, 31, 57, 82, 5, 8, 9, 10, 11, 13, 243, 336,354, 416, 173, 175, 182, 211, 85, 105, 122, 127, 15, 16, 18, 20, 22, 429316, 328, 333, 334, 133, 148, 155, 161, 23, 24, 25, 26, 27, 337, 353,425, 434, 205, 210, 220, 226, 28, 32, 33, 34, 35, 441 228, 241, 242,246, 36, 37, 38, 39, 40, 276, 279, 285, 303, 41, 42, 43, 44, 45, 312,326, 327, 329, 46, 47, 48, 49, 50, 335, 338, 356, 359, 51, 52, 53, 55,59, 366, 380, 396, 401, 60, 61, 62, 63, 65, 402, 422, 424, 428, 66, 68,70, 72, 74, 430, 432, 435, 440 76, 89, 91, 94, 96, 98, 100, 102, 104,106, 107, 108, 112, 113, 115, 116, 124, 125, 126, 129, 130, 132, 136,138, 140, 145, 151, 152, 153, 154, 156, 157, 159, 163, 164, 165, 166,167, 168, 169, 177, 179, 181, 183, 185, 187, 189, 191, 192, 193, 196,199, 203, 204, 206, 207, 214, 217, 222, 223, 224, 230, 231, 232, 233,234, 235, 249, 252, 255, 258, 261, 264, 267, 270, 273, 282, 288, 291,297, 300, 306, 309, 325, 332, 360, 361, 364, 365, 367, 368, 369, 370,371, 372, 373, 374, 375, 376, 378, 379, 382, 383, 387, 389, 391, 393,394, 397, 399, 403, 408, 410, 412, 413, 414, 415, 417, 418, 419, 431,433, 436, 442, 443 PI3K α 11, 12, 16, 22, 30, 5, 8, 13, 15, 18, 20, 9,10, 23, 25, 26, 27, 13, 36, 50, 53, 89, 31, 60, 63, 75, 77, 24, 32, 33,35, 38, 28, 34, 37, 39, 40, 192, 364, 370 78, 76, 82, 85, 92, 41, 42,43, 44, 45, 46, 47, 48, 49, 65, 104, 111, 114, 119, 51, 52, 55, 57, 59,96, 100, 106, 107, 122, 124, 128, 130, 61, 62, 65, 66, 68, 112, 113,115, 129, 132, 145, 148, 151, 70, 72, 74, 91, 94, 140, 153, 157, 181,154, 155, 159, 161, 98, 102, 105, 108, 193, 223, 233, 235, 163, 166,168, 171, 116, 125, 126, 127, 374, 394, 413, 415, 173, 175, 179, 182,133, 136, 138, 152, 431 204, 205, 210, 211, 156, 164, 165, 167, 214,220, 226, 228, 169, 177, 183, 185, 242, 243, 246, 252, 187, 189, 191,196, 258, 261, 270, 273, 199, 203, 206, 207, 276, 279, 282, 288, 217,222, 224, 230, 291, 297, 303, 306, 231, 232, 234, 241, 312, 328, 333,334, 249, 255, 264, 267, 335, 336, 353, 354, 285, 300, 309, 316, 356,366, 367, 368, 325, 326, 327, 329, 372, 373, 375, 376, 332, 337, 338,359, 378, 379, 380, 382, 360, 361, 365, 369, 387, 391, 393, 402, 371,383, 389, 396, 403, 410, 412, 419, 397, 399, 401, 408, 429, 430, 432,433, 414, 416, 417, 418, 434, 435, 436, 440, 422, 424, 425, 428, 441,442 443 PI3K β 5, 11, 12, 20, 22, 31, 10, 13, 16, 23, 24, 9, 15, 18, 25,33, 39, 8, 89, 107, 129, 223, 41, 55, 57, 60, 63, 26, 27, 28, 30, 32,47, 50, 59, 72, 76, 249, 309, 325, 369, 75, 77, 78, 82, 85, 34, 35, 36,37, 38, 91, 99, 106, 108, 370, 394, 431 92, 96, 111, 112, 40, 42, 43,44, 45, 113, 136, 157, 193, 114, 119, 122, 127, 46, 48, 49, 51, 52, 199,217, 222, 255, 128, 130, 132, 133, 53, 61, 62, 66, 68, 264, 267, 276,285, 148, 151, 152, 154, 70, 74, 94, 98, 100, 297, 306, 332, 360, 155,156, 159, 161, 102, 104, 105, 115, 361, 364, 365, 371, 163, 164, 165,169, 116, 124, 125, 126, 372, 374, 410, 413, 171, 173, 175, 177, 138,140, 145, 153, 415, 416, 418, 419, 179, 182, 185, 203, 166, 167, 168,181, 440 204, 205, 206, 211, 183, 187, 189, 191, 226, 228, 231, 242,192, 196, 207, 210, 243, 273, 312, 316, 214, 220, 224, 230, 327, 328,333, 334, 232, 233, 234, 235, 335, 336, 337, 353, 241, 246, 252, 258,354, 356, 378, 379, 261, 270, 279, 282, 380, 383, 387, 391, 288, 291,300, 303, 393, 414, 422, 424, 326, 329, 338, 359, 425, 429, 430, 432,366, 367, 368, 373, 433, 434, 435, 441, 375, 376, 382, 389, 442 396,397, 399, 401, 402, 403, 408, 412, 417, 428, 436, 443 B cellproliferation 82, 204, 211, 441 92, 161, 163, 246, 5, 8, 9, 10, 12, 13,EC50 (nM) 252, 432 15, 16, 18, 20, 22, 23, 24, 25, 26, 27, 28, 30, 31,41, 42, 43, 44, 45, 47, 48, 49, 50, 51, 52, 55, 57, 59, 60, 61, 62, 63,66, 72, 74, 79, 89, 91, 94, 96, 98, 100, 102, 105, 106, 107, 108, 112,115, 116, 124, 125, 126, 129, 130, 136, 140, 151, 152, 153, 156, 159,164, 165, 166, 167, 169, 177, 181, 183, 185, 187, 189, 192, 193, 196,199, 203, 206, 207, 217, 222, 223, 224, 230, 231, 232, 233, 234, 249,297, 300, 306, 309, 325, 332, 360, 361, 365, 367, 369, 371, 372, 380,431, 440, 443

TABLE 5 Structures of the Compounds for the IC₅₀ results described inTable 4 above and other exemplary compounds Structure

Compound 5

Compound 8

Compound 9

Compound 10

Compound 11

Compound 12

Compound 13

Compound 15

Compound 16

Compound 18

Compound 20

Compound 22

Compound 23

Compound 24

Compound 25

Compound 26

Compound 27

Compound 28

Compound 30

Compound 31

Compound 32

Compound 33

Compound 34

Compound 35

Compound 36

Compound 37

Compound 38

Compound 39

Compound 40

Compound 41

Compound 42

Compound 43

Compound 44

Compound 45

Compound 46

Compound 47

Compound 48

Compound 49

Compound 50

Compound 51

Compound 52

Compound 53

Compound 55

Compound 57

Compound 59

Compound 60

Compound 61

Compound 62

Compound 63

Compound 65

Compound 66

Compound 68

Compound 70

Compound 72

Compound 74

Compound 75

Compound 76

Compound 77

Compound 78

Compound 82

Compound 85

Compound 89

Compound 91

Compound 92

Compound 94

Compound 96

Compound 98

Compound 100

Compound 102

Compound 104

Compound 105

Compound 106

Compound 107

Compound 108

Compound 111

Compound 112

Compound 113

Compound 114

Compound 115

Compound 116

Compound 119

Compound 122

Compound 124

Compound 125

Compound 126

Compound 127

Compound 128

Compound 129

Compound 130

Compound 132

Compound 133

Compound 136

Compound 138

Compound 140

Compound 145

Compound 148

Compound 151

Compound 152

Compound 153

Compound 154

Compound 155

Compound 156

Compound 157

Compound 159

Compound 161

Compound 163

Compound 164

Compound 165

Compound 166

Compound 167

Compound 168

Compound 169

Compound 171

Compound 173

Compound 175

Compound 177

Compound 179

Compound 181

Compound 182

Compound 183

Compound 185

Compound 187

Compound 189

Compound 191

Compound 192

Compound 193

Compound 196

Compound 199

Compound 203

Compound 204

Compound 205

Compound 206

Compound 207

Compound 210

Compound 211

Compound 214

Compound 217

Compound 220

Compound 222

Compound 223

Compound 224

Compound 226

Compound 228

Compound 229

Compound 230

Compound 231

Compound 232

Compound 233

Compound 234

Compound 235

Compound 241

Compound 242

Compound 243

Compound 246

Compound 249

Compound 252

Compound 255

Compound 258

Compound 261

Compound 264

Compound 267

Compound 270

Compound 273

Compound 276

Compound 279

Compound 282

Compound 285

Compound 288

Compound 291

Compound 294

Compound 297

Compound 300

Compound 303

Compound 306

Compound 309

Compound 312

Compound 313

Compound 316

Compound 319

Compound 322

Compound 325

Compound 326

Compound 327

Compound 328

Compound 329

Compound 332

Compound 333

Compound 334

Compound 335

Compound 336

Compound 337

Compound 338

Compound 353

Compound 354

Compound 356

Compound 359

Compound 360

Compound 361

Compound 364

Compound 365

Compound 366

Compound 367

Compound 368

Compound 369

Compound 370

Compound 371

Compound 372

Compound 373

Compound 374

Compound 375

Compound 376

Compound 378

Compound 379

Compound 380

Compound 381

Compound 382

Compound 383

Compound 384

Compound 385

Compound 387

Compound 389

Compound 391

Compound 393

Compound 394

Compound 396

Compound 397

Compound 398

Compound 399

Compound 400

Compound 401

Compound 402

Compound 403

Compound 404

Compound 405

Compound 406

Compound 407

Compound 408

Compound 409

Compound 410

Compound 412

Compound 413

Compound 414

Compound 415

Compound 416

Compound 417

Compound 418

Compound 419

Compound 420

Compound 422

Compound 424

Compound 425

Compound 428

Compound 429

Compound 430

Compound 431

Compound 432

Compound 433

Compound 434

Compound 435

Compound 436

Compound 437

Compound 438

Compound 439

Compound 440

Compound 441

Compound 442

Compound 443

Compound 444

Compound 445

Compound 446

Compound 447

Compound 448

Compound 449

Compound 450

Compound 451

Compound 452

Compound 453

Compound 454

Compound 455

Compound 456

Compound 457

Compound 458

Compound 459

Compound 460

Compound 461

Compound 462

Biological Activity Assessment

A PI3-Kinase HTRF® assay kit (cat No. 33-016) purchased from MilliporeCorporation was used to screen compounds provided herein. This assayused specific, high affinity binding of the GRP1 pleckstrin homology(PH) domain to PIP3, the product of a Class 1A or 1B PI3 Kinase actingon its physiological substrate PIP2. During the detection phase of theassay, a complex was generated between the GST-tagged PH domain andbiotinylated short chain PIP3. The biotinylated PIP3 and the GST-taggedPH domain recruited fluorophores (Streptavidin-Allophycocyanin andEuropium-labeled anti-GST respectively) to form the fluorescenceresonance energy transfer (FRET) architecture, generating a stabletime-resolved FRET signal. The FRET complex was disrupted in acompetitive manner by non-biotinylated PIP3, a product formed in the PI3Kinase assay.

PI3 Kinase α, β, γ and δ activity was assayed using the PI3 Kinase HTRF®assay kit (catalogue No. 33-016) purchased from Millipore Corporation.Purified recombinant PI3Kα (catalogue No. 14-602-K), PI3Kβ (catalogueNo. 14-603-K), PI3Kγ(catalogue No. 14-558-K) and PI3Kδ (catalogue No.14-604-K) were obtained from Millipore Corporation. Purified recombinantPI3K enzyme was used to catalyze the phosphorylation ofphosphatidylinositol 4,5-bisphosphate (PIP2 at 10 μM) tophosphatidylinositol 3,4,5-trisphosphate (PIP3) in the presence of 10 μMATP. The assay was carried out in 384-well format and detected using aPerkin Elmer EnVision Xcite Multilabel Reader. Emission ratios wereconverted into percent inhibitions and imported into GraphPad Prismsoftware. The concentration necessary to achieve inhibition of enzymeactivity by 50% (IC₅₀) was calculated using concentrations ranging from20 μM to 0.1 nM (12-point curve). IC₅₀ values were determined using anonlinear regression model available in GraphPad Prism 5.

Example 259: Chemical Stability

The chemical stability of one or more subject compounds is determinedaccording to standard procedures known in the art. The following detailsan exemplary procedure for ascertaining chemical stability of a subjectcompound. The default buffer used for the chemical stability assay isphosphate-buffered saline (PBS) at pH 7.4; other suitable buffers can beused. A subject compound is added from a 100 μM stock solution to analiquot of PBS (in duplicate) to give a final assay volume of 400 μL,containing 5 μM test compound and 1% DMSO (for half-life determination atotal sample volume of 700 μL is prepared). Reactions are incubated,with shaking, for 24 hours at 37° C.; for half-life determinationsamples are incubated for 0, 2, 4, 6, and 24 hours. Reactions arestopped by adding immediately 100 μL of the incubation mixture to 100 μLof acetonitrile and vortexing for 5 minutes. The samples are then storedat −20° C. until analysis by HPLC-MS/MS. Where desired, a controlcompound or a reference compound such as chlorambucil (5 μM) is testedsimultaneously with a subject compound of interest, as this compound islargely hydrolyzed over the course of 24 hours. Samples are analyzed via(RP)HPLC-MS/MS using selected reaction monitoring (SRM). The HPLCconditions consist of a binary LC pump with autosampler, a mixed-mode,C12, 2×20 mm column, and a gradient program. Peak areas corresponding tothe analytes are recorded by HPLC-MS/MS. The ratio of the parentcompound remaining after 24 hours relative to the amount remaining attime zero, expressed as percent, is reported as chemical stability. Incase of half-life determination, the half-life is estimated from theslope of the initial linear range of the logarithmic curve of compoundremaining (%) vs. time, assuming first order kinetics.

Example 260: Expression and Inhibition Assays of p110α/p85α, p110β/p85α,p110δ/p85α, and p110γ

Class I PI3-Ks can be either purchased (p110α/p85α, p110β/p85α,p110δ/p85α from Upstate, and p110γ from Sigma) or expressed aspreviously described (Knight et al., 2004). IC₅₀ values are measuredusing either a standard TLC assay for lipid kinase activity (describedbelow) or a high-throughput membrane capture assay. Kinase reactions areperformed by preparing a reaction mixture containing kinase, inhibitor(2% DMSO final concentration), buffer (25 mM HEPES, pH 7.4, 10 mMMgCl2), and freshly sonicated phosphatidylinositol (100 μg/ml).Reactions are initiated by the addition of ATP containing 10 μCi ofγ-32P-ATP to a final concentration of 10 or 100 μM and allowed toproceed for 5 minutes at room temperature. For TLC analysis, reactionsare then terminated by the addition of 105 μl 1N HCl followed by 160 μlCHCl₃:MeOH (1:1). The biphasic mixture is vortexed, briefly centrifuged,and the organic phase is transferred to a new tube using a gel loadingpipette tip precoated with CHCl₃. This extract is spotted on TLC platesand developed for 3-4 hours in a 65:35 solution of n-propanol:1M aceticacid. The TLC plates are then dried, exposed to a phosphorimager screen(Storm, Amersham), and quantitated. For each compound, kinase activityis measured at 10-12 inhibitor concentrations representing two-folddilutions from the highest concentration tested (typically, 200 μM). Forcompounds showing significant activity, IC₅₀ determinations are repeatedtwo to four times, and the reported value is the average of theseindependent measurements.

Other commercial kits or systems for assaying PI3-K activities areavailable. The commercially available kits or systems can be used toscreen for inhibitors and/or agonists of PI3-Ks including, but notlimited to, PI 3-Kinase α, β, δ, and γ. An exemplary system is PI3-Kinase (human) HTRF™ Assay from Upstate. The assay can be carried outaccording to the procedures suggested by the manufacturer. Briefly, theassay is a time resolved FRET assay that indirectly measures PIP3product formed by the activity of a PI3-K. The kinase reaction isperformed in a microtiter plate (e.g., a 384 well microtiter plate). Thetotal reaction volume is approximately 20 μl per well. In the firststep, each well receives 2 μl of test compound in 20% dimethylsulphoxideresulting in a 2% DMSO final concentration. Next, approximately 14.5 μlof a kinase/PIP2 mixture (diluted in 1× reaction buffer) is added perwell for a final concentration of 0.25-0.3 μg/ml kinase and 10 μM PIP2.The plate is sealed and incubated for 15 minutes at room temperature. Tostart the reaction, 3.5 μl of ATP (diluted in 1× reaction buffer) isadded per well for a final concentration of 10 μM ATP. The plate issealed and incubated for 1 hour at room temperature. The reaction isstopped by adding 5 μl of Stop Solution per well and then 5 μl ofDetection Mix is added per well. The plate is sealed, incubated for 1hour at room temperature, and then read on an appropriate plate reader.Data is analyzed and IC₅₀s are generated using GraphPad Prism 5.

Example 261: B Cell Activation and Proliferation Assay

The ability of one or more subject compounds to inhibit B cellactivation and proliferation is determined according to standardprocedures known in the art. For example, an in vitro cellularproliferation assay is established that measures the metabolic activityof live cells. The assay is performed in a 96 well microtiter plateusing Alamar Blue reduction. Balb/c splenic B cells are purified over aFicoll-Paque™ PLUS gradient followed by magnetic cell separation using aMACS B cell Isolation Kit (Miletenyi). Cells are plated in 90 μl at50,000 cells/well in B Cell Media (RPMI+10% FBS+Penn/Strep+50 μM bME+5mM HEPES). A compound provided herein is diluted in B Cell Media andadded in a 10 μl volume. Plates are incubated for 30 min at 37° C. and5% CO₂ (0.2% DMSO final concentration). A 50 μl B cell stimulationcocktail is then added containing either 10 μg/ml LPS or 5 g/ml F(ab′)2Donkey anti-mouse IgM plus 2 ng/ml recombinant mouse IL4 in B CellMedia. Plates are incubated for 72 hours at 37° C. and 5% CO₂. A volumeof 15 μL of Alamar Blue reagent is added to each well and plates areincubated for 5 hours at 37° C. and 5% CO₂. Alamar Blue fluoresce isread at 560Ex/590Em, and IC₅₀ or EC₅₀ values are calculated usingGraphPad Prism 5.

Example 262: Tumor Cell Line Proliferation Assay

The ability of one or more subject compounds to inhibit tumor cell lineproliferation can be determined according to standard procedures knownin the art. For instance, an in vitro cellular proliferation assay canbe performed to measure the metabolic activity of live cells. The assayis performed in a 96 well microtiter plate using Alamar Blue reduction.Human tumor cell lines are obtained from ATCC (e.g., MCF7, U-87 MG,MDA-MB-468, PC-3), grown to confluency in T75 flasks, trypsinized with0.25% trypsin, washed one time with Tumor Cell Media (DMEM+10% FBS), andplated in 90 μl at 5,000 cells/well in Tumor Cell Media. A compoundprovided herein is diluted in Tumor Cell Media and added in a 10 μlvolume. Plates are incubated for 72 hours at 37° C. and 5% CO₂. A volumeof 10 μL of Alamar Blue reagent is added to each well and plates areincubated for 3 hours at 37° C. and 5% CO₂. Alamar Blue fluoresce isread at 560Ex/590Em, and IC₅₀ values are calculated using GraphPad Prism5.

Example 263: Antitumor Activity In Vivo

The compounds described herein can be evaluated in a panel of human andmurine tumor models.

Paclitaxel-Refractory Tumor Models

1. Clinically-Derived Ovarian Carcinoma Model.

This tumor model is established from a tumor biopsy of an ovarian cancerpatient. Tumor biopsy is taken from the patient. The compounds describedherein are administered to nude mice bearing staged tumors using anevery 2 days×5 schedule.

2. A2780Tax Human Ovarian Carcinoma Xenograft (Mutated Tubulin).

A2780Tax is a paclitaxel-resistant human ovarian carcinoma model. It isderived from the sensitive parent A2780 line by co-incubation of cellswith paclitaxel and verapamil, an MDR-reversal agent. Its resistancemechanism has been shown to be non-MDR related and is attributed to amutation in the gene encoding the beta-tubulin protein. The compoundsdescribed herein can be administered to mice bearing staged tumors on anevery 2 days×5 schedule.

3. HCT116/VM46 Human Colon Carcinoma Xenograft (Multi-Drug Resistant).

HCT116/VM46 is an MDR-resistant colon carcinoma developed from thesensitive HCT116 parent line. In vivo, grown in nude mice, HCT116/VM46has consistently demonstrated high resistance to paclitaxel. Thecompounds described herein can be administered to mice bearing stagedtumors on an every 2 days×5 schedule.

4. M5076 Murine Sarcoma Model

M5076 is a mouse fibrosarcoma that is inherently refractory topaclitaxel in vivo. The compounds described herein can be administeredto mice bearing staged tumors on an every 2 days×5 schedule.

One or more compounds as provided herein can be used in combinationother therapeutic agents in vivo in the multidrug resistant human coloncarcinoma xenografts HCT/VM46 or any other model known in the artincluding those described herein.

Example 264: Microsome Stability Assay

The stability of one or more subject compounds is determined accordingto standard procedures known in the art. For example, stability of oneor more subject compounds is established by an in vitro assay. Forexample, an in vitro microsome stability assay is established thatmeasures stability of one or more subject compounds when reacting withmouse, rat or human microsomes from liver. The microsome reaction withcompounds is performed in 1.5 mL Eppendorf tube. Each tube contains 0.1μL of 10.0 mg/ml NADPH; 75 μL of 20.0 mg/ml mouse, rat or human livermicrosome; 0.4 μL of 0.2 M phosphate buffer, and 425 μL of ddH₂O.Negative control (without NADPH) tube contains 75 μL of 20.0 mg/mlmouse, rat or human liver microsome; 0.4 L of 0.2 M phosphate buffer,and 525 μL of ddH₂O. The reaction is started by adding 1.0 μL of 10.0 mMtested compound. The reaction tubes are incubated at 37° C. 100 μLsample is collected into new Eppendorf tube containing 300 μL coldmethanol at 0, 5, 10, 15, 30 and 60 minutes of reaction. Samples arecentrifuged at 15,000 rpm to remove protein. Supernatant of centrifugedsample is transferred to new tube. Concentration of stable compoundafter reaction with microsome in the supernatant is measured by LiquidChromatography/Mass Spectrometry (LC-MS).

Example 265: Plasma Stability Assay

The stability of one or more subject compounds in plasma is determinedaccording to standard procedures known in the art. See, e.g., RapidCommun. Mass Spectrom., 10: 1019-1026. The following procedure is anHPLC-MS/MS assay using human plasma; other species including monkey,dog, rat, and mouse are also available. Frozen, heparinized human plasmais thawed in a cold water bath and spun for 10 minutes at 2000 rpm at 4°C. prior to use. A subject compound is added from a 400 M stock solutionto an aliquot of pre-warmed plasma to give a final assay volume of 400μL (or 800 μL for half-life determination), containing 5 M test compoundand 0.5% DMSO. Reactions are incubated, with shaking, for 0 minutes and60 minutes at 37° C., or for 0, 15, 30, 45 and 60 minutes at 37 C forhalf life determination. Reactions are stopped by transferring 50 μL ofthe incubation mixture to 200 μL of ice-cold acetonitrile and mixed byshaking for 5 minutes. The samples are centrifuged at 6000×g for 15minutes at 4° C. and 120 μL of supernatant removed into clean tubes. Thesamples are then evaporated to dryness and submitted for analysis byHPLC-MS/MS.

In one embodiment, one or more control or reference compounds (5 μM) aretested simultaneously with the test compounds: one compound,propoxycaine, with low plasma stability and another compound,propantheline, with intermediate plasma stability.

Samples are reconstituted in acetonitrile/methanol/water (1/1/2, v/v/v)and analyzed via (RP)HPLC-MS/MS using selected reaction monitoring(SRM). The HPLC conditions consist of a binary LC pump with autosampler,a mixed-mode, C12, 2×20 mm column, and a gradient program. Peak areascorresponding to the analytes are recorded by HPLC-MS/MS. The ratio ofthe parent compound remaining after 60 minutes relative to the amountremaining at time zero, expressed as percent, is reported as plasmastability. In case of half-life determination, the half-life isestimated from the slope of the initial linear range of the logarithmiccurve of compound remaining (%) vs. time, assuming first order kinetics.

Example 266: Kinase Signaling in Blood

PI3K/Akt/mTor signaling is measured in blood cells using the phosflowmethod (Methods Enzymol. (2007) 434:131-54). This method is by nature asingle cell assay so that cellular heterogeneity can be detected ratherthan population averages. This allows concurrent distinction ofsignaling states in different populations defined by other markers.Phosflow is also highly quantitative. To test the effects of one or morecompounds provided herein, unfractionated splenocytes, or peripheralblood mononuclear cells are stimulated with anti-CD3 to initiate T-cellreceptor signaling. The cells are then fixed and stained for surfacemarkers and intracellular phosphoproteins. Inhibitors provided hereininhibit anti-CD3 mediated phosphorylation of Akt-S473 and S6, whereasrapamycin inhibits S6 phosphorylation and enhances Akt phosphorylationunder the conditions tested.

Similarly, aliquots of whole blood are incubated for 15 minutes withvehicle (e.g., 0.1% DMSO) or kinase inhibitors at variousconcentrations, before addition of stimuli to crosslink the T cellreceptor (TCR) (anti-CD3 with secondary antibody) or the B cell receptor(BCR) using anti-kappa light chain antibody (Fab′2 fragments). Afterapproximately 5 and 15 minutes, samples are fixed (e.g., with cold 4%paraformaldehyde) and used for phosflow. Surface staining is used todistinguish T and B cells using antibodies directed to cell surfacemarkers that are known to the art. The level of phosphorylation ofkinase substrates such as Akt and S6 are then measured by incubating thefixed cells with labeled antibodies specific to the phosphorylatedisoforms of these proteins. The population of cells are then analyzed byflow cytometry.

Example 267: Colony Formation Assay

Murine bone marrow cells freshly transformed with a p190 BCR-Ablretrovirus (herein referred to as p190 transduced cells) are plated inthe presence of various drug combinations in M3630 methylcellulose mediafor about 7 days with recombinant human IL-7 in about 30% serum, and thenumber of colonies formed is counted by visual examination under amicroscope.

Alternatively, human peripheral blood mononuclear cells are obtainedfrom Philadelphia chromosome positive (Ph+) and negative (Ph−) patientsupon initial diagnosis or relapse. Live cells are isolated and enrichedfor CD19+CD34+ B cell progenitors. After overnight liquid culture, cellsare plated in methocult GF+H4435, Stem Cell Technologies) supplementedwith cytokines (IL-3, IL-6, IL-7, G-CSF, GM-CSF, CF, Flt3 ligand, anderythropoietin) and various concentrations of known chemotherapeuticagents in combination with either compounds of the present disclosure.Colonies are counted by microscopy 12-14 days later. This method can beused to test for evidence of additive or synergistic activity.

Example 268: In Vivo Effect of Kinase Inhibitors on Leukemic Cells

Female recipient mice are lethally irradiated from a γ source in twodoses about 4 hr apart, with approximately 5Gy each. About 1 hr afterthe second radiation dose, mice are injected i.v. with about 1×10⁶leukemic cells (e.g., Ph+ human or murine cells, or p190 transduced bonemarrow cells). These cells are administered together with aradioprotective dose of about 5×10⁶ normal bone marrow cells from 3-5week old donor mice. Recipients are given antibiotics in the water andmonitored daily. Mice who become sick after about 14 days are euthanizedand lymphoid organs are harvested for analysis. Kinase inhibitortreatment begins about 10 days after leukemic cell injection andcontinues daily until the mice become sick or a maximum of approximately35 days post-transplant. Inhibitors are given by oral lavage.

Peripheral blood cells are collected approximately on day 10(pre-treatment) and upon euthanization (post treatment), contacted withlabeled anti-hCD4 antibodies and counted by flow cytometry. This methodcan be used to demonstrate that the synergistic effect of one or morecompounds provided herein in combination with known chemotherapeuticagents can reduce leukemic blood cell counts as compared to treatmentwith known chemotherapeutic agents (e.g., Gleevec) alone under theconditions tested.

Example 269: Treatment of Lupus Disease Model Mice

Mice lacking the inhibitory receptor FcγRIIb that opposes PI3K signalingin B cells develop lupus with high penetrance. FcγRIIb knockout mice(R²KO, Jackson Labs) are considered a valid model of the human diseaseas some lupus patients show decreased expression or function of FcγRIIb(S. Bolland and J. V. Ravtech 2000. Immunity 12:277-285).

The R²KO mice develop lupus-like disease with anti-nuclear antibodies,glomerulonephritis and proteinurea within about 4-6 months of age. Forthese experiments, the rapamycin analogue RAD001 (available from LCLaboratories) is used as a benchmark compound, and administered orally.This compound has been shown to ameliorate lupus symptoms in theB6.Slelz.Sle3z model (T. Wu et al. J. Clin Invest. 117:2186-2196).

The NZB/W F1 mice spontaniously develop a systemic autoimmune diseasewith that is a model of lupus. The mice are treated starting at 20 weeksof age for a profilactic model and at 23 weeks of age for a therapeuticmodel. Blood and urine samples are obtained at approximately throughoutthe testing period, and tested for antinuclear antibodies (in dilutionsof serum) or protein concentration (in urine). Serum is also tested foranti-ssDNA and anti-dsDNA antibodies by ELISA. Glomerulonephritis isassessed in kidney sections stained with H&E at the end of the study, orsurvival can be an endpoint. For example, the proteozome inhibitorBortezimib is effective at blocking disease in the NZB/W model in boththe profilactic and therapeuctic model with reductions in auto-antibodyproduction, kidney damage, and improvements in survival (Nature Medicine14, 748-755 (2008)).

Lupus disease model mice such as R²KO, BXSB or MLR/lpr are treated atabout 2 months old, approximately for about two months. Mice are givendoses of: vehicle, RAD001 at about 10 mg/kg, or compounds providedherein at approximately 1 mg/kg to about 500 mg/kg. Blood and urinesamples are obtained at approximately throughout the testing period, andtested for antinuclear antibodies (in dilutions of serum) or proteinconcentration (in urine). Serum is also tested for anti-ssDNA andanti-dsDNA antibodies by ELISA. Animals are euthanized at day 60 andtissues harvested for measuring spleen weight and kidney disease.Glomerulonephritis is assessed in kidney sections stained with H&E.Other animals are studied for about two months after cessation oftreatment, using the same endpoints.

This established art model can be employed to demonstrate that thekinase inhibitors provided herein can suppress or delay the onset oflupus symptoms in lupus disease model mice.

Example 270: Murine Bone Marrow Transplant Assay

Female recipient mice are lethally irradiated from a γ ray source. About1 hr after the radiation dose, mice are injected with about 1×106leukemic cells from early passage p190 transduced cultures (e.g., asdescribed in Cancer Genet Cytogenet. 2005 August; 161(1):51-6). Thesecells are administered together with a radioprotective dose ofapproximately 5×10⁶ normal bone marrow cells from 3-5 wk old donor mice.Recipients are given antibiotics in the water and monitored daily. Micewho become sick after about 14 days are euthanized and lymphoid organsharvested for flow cytometry and/or magnetic enrichment. Treatmentbegins on approximately day 10 and continues daily until mice becomesick, or after a maximum of about 35 days post-transplant. Drugs aregiven by oral gavage (p.o.). In a pilot experiment a dose ofchemotherapeutic that is not curative but delays leukemia onset by aboutone week or less is identified; controls are vehicle-treated or treatedwith chemotherapeutic agent, previously shown to delay but not cureleukemogenesis in this model (e.g., imatinib at about 70 mg/kg twicedaily). For the first phase p190 cells that express eGFP are used, andpostmortem analysis is limited to enumeration of the percentage ofleukemic cells in bone marrow, spleen and lymph node (LN) by flowcytometry. In the second phase, p190 cells that express a tailless formof human CD4 are used and the postmortem analysis includes magneticsorting of hCD4+ cells from spleen followed by immunoblot analysis ofkey signaling endpoints: p Akt-T308 and S473; pS6 and p4EBP-1. Ascontrols for immunoblot detection, sorted cells are incubated in thepresence or absence of kinase inhibitors of the present disclosureinhibitors before lysis. Optionally, “phosflow” is used to detect pAkt-S473 and pS6-S235/236 in hCD4-gated cells without prior sorting.These signaling studies are particularly useful if, for example,drug-treated mice have not developed clinical leukemia at the 35 daytime point. Kaplan-Meier plots of survival are generated and statisticalanalysis done according to methods known in the art. Results from p190cells are analyzed separated as well as cumulatively.

Samples of peripheral blood (100-200 μl) are obtained weekly from allmice, starting on day 10 immediately prior to commencing treatment.Plasma is used for measuring drug concentrations, and cells are analyzedfor leukemia markers (eGFP or hCD4) and signaling biomarkers asdescribed herein.

This general assay known in the art can be used to demonstrate thateffective therapeutic doses of the compounds provided herein can be usedfor inhibiting the proliferation of leukemic cells.

Example 271: Matrigel Plug Angiogenesis Assay

Matrigel containing test compounds are injected subcutaneously orintraocularly, where it solidifies to form a plug. The plug is recoveredafter 7-21 days in the animal and examined histologically to determinethe extent to which blood vessels have entered it. Angiogenesis ismeasured by quantification of the vessels in histologic sections.Alternatively, fluorescence measurement of plasma volume is performedusing fluorescein isothiocyanate (FITC)-labeled dextran 150. The resultsare expected to indicate one or more compounds provided herein thatinhibit angiogenesis and are thus expected to be useful in treatingocular disorders related to aberrant angiogenesis and/or vascularpermeability.

Example 272: Corneal Angiogenesis Assay

A pocket is made in the cornea, and a plug containing an angiogenesisinducing formulation (e.g., VEGF, FGF, or tumor cells), when introducedinto this pocket, elicits the ingrowth of new vessels from theperipheral limbal vasculature. Slow-release materials such as ELVAX(ethylene vinyl copolymer) or Hydron are used to introduce angiogenesisinducing substances into the corneal pocket. Alternatively, a spongematerial is used.

The effect of putative inhibitors on the locally induced (e.g., spongeimplant) angiogenic reaction in the cornea (e.g., by FGF, VEGF, or tumorcells). The test compound is administered orally, systemically, ordirectly to the eye. Systemic administration is by bolus injection or,more effectively, by use of a sustained-release method such asimplantation of osmotic pumps loaded with the test inhibitor.Administration to the eye is by any of the methods described hereinincluding, but not limited to eye drops, topical administration of acream, emulsion, or gel, intravitreal injection.

The vascular response is monitored by direct observation throughout thecourse of the experiment using a stereomicroscope in mice. Definitivevisualization of the corneal vasculature is achieved by administrationof fluorochrome-labeled high-molecular weight dextran. Quantification isperformed by measuring the area of vessel penetration, the progress ofvessels toward the angiogenic stimulus over time, or in the case offluorescence, histogram analysis or pixel counts above a specific(background) threshold.

The results can indicate one or more compounds provided herein inhibitangiogenesis and thus can be useful in treating ocular disorders relatedto aberrant angiogenesis and/or vascular permeability.

Example 273: Microtiter-Plate Angiogenesis Assay

The assay plate is prepared by placing a collagen plug in the bottom ofeach well with 5-10 cell spheroids per collagen plug each spheroidcontaining 400-500 cells. Each collagen plug is covered with 1100 μl ofstorage medium per well and stored for future use (1-3 days at 37° C.,5% CO₂). The plate is sealed with sealing. Test compounds are dissolvedin 200 μl assay medium with at least one well including a VEGF positivecontrol and at least one well without VEGF or test compound as anegative control. The assay plate is removed from the incubator andstorage medium is carefully pipeted away. Assay medium containing thetest compounds are pipeted onto the collagen plug. The plug is placed ina humidified incubator for (37° C., 5% CO₂) 24-48 hours. Angiogenesis isquantified by counting the number of sprouts, measuring average sproutlength, or determining cumulative sprout length. The assay can bepreserved for later analysis by removing the assay medium, adding 1 mlof 10% paraformaldehyde in Hanks BSS per well, and storing at 4° C. Theresults are expected to identify compounds that inhibit angiogenesis invarious cell types tested, including cells of ocular origin.

Example 274: Combination Use of PI3K-δ Inhibitors and Agents thatInhibit IgE Production or Activity

The compounds as provided herein can present synergistic or additiveefficacy when administered in combination with agents that inhibit IgEproduction or activity. Agents that inhibit IgE production include, forexample, one or more of TEI-9874,2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid,rapamycin, rapamycin analogs (i.e., rapalogs), TORC1 inhibitors, TORC2inhibitors, and any other compounds that inhibit mTORC1 and mTORC2.Agents that inhibit IgE activity include, for example, anti-IgEantibodies such as Omalizumab and TNX-901.

One or more of the subject compounds capable of inhibiting PI3K-δ can beefficacious in treatment of autoimmune and inflammatory disorders(AIID), for example, rheumatoid arthritis. If any of the compoundscauses an undesired level of IgE production, one can choose toadminister it in combination with an agent that inhibits IgE productionor IgE activity. Additionally, the administration of PI3K-δ or PI3K-δ/γinhibitors as provided herein in combination with inhibitors of mTOR canalso exhibit synergy through enhanced inhibition of the PI3K pathway.Various in vivo and in vitro models can be used to establish the effectof such combination treatment on AIID including, but not limited to (a)in vitro B-cell antibody production assay, (b) in vivo TNP assay, and(c) rodent collagen induced arthritis model.

(a) B-Cell Assay

Mice are euthanized, and the spleens are removed and dispersed through anylon mesh to generate a single-cell suspension. The splenocytes arewashed (following removal of erythrocytes by osmotic shock) andincubated with anti-CD43 and anti-Mac-1 antibody-conjugated microbeads(Miltenyi Biotec). The bead-bound cells are separated from unbound cellsusing a magnetic cell sorter. The magnetized column retains the unwantedcells and the resting B cells are collected in the flow-through.Purified B-cells are stimulated with lipopolysaccharide or an anti-CD40antibody and interleukin 4. Stimulated B-cells are treated with vehiclealone or with PI3K-δ inhibitors as provided herein with and without mTORinhibitors such as rapamycin, rapalogs, or mTORC1/C2 inhibitors. Theresults are expected to show that in the presence of mTOR inhibitors(e.g., rapamycin) alone, there is little to no substantial effect on IgGand IgE response. However, in the presence of PI3K-δ and mTORinhibitors, the B-cells are expected to exhibit a decreased IgG responseas compared to the B-cells treated with vehicle alone, and the B-cellsare expected to exhibit a decreased IgE response as compared to theresponse from B-cells treated with PI3K-δ inhibitors alone.

(b) TNP Assay

Mice are immunized with TNP-Ficoll or TNP-KHL and treated with: vehicle,a PI3K-δ inhibitor, an mTOR inhibitor, for example rapamycin, or aPI3K-δ inhibitor in combination with an mTOR inhibitor such asrapamycin. Antigen-specific serum IgE is measured by ELISA using TNP-BSAcoated plates and isotype specific labeled antibodies. It is expectedthat mice treated with an mTOR inhibitor alone exhibit little or nosubstantial effect on antigen specific IgG3 response and nostatistically significant elevation in IgE response as compared to thevehicle control. It is also expected that mice treated with both PI3K-δinhibitor and mTOR inhibitor exhibit a reduction in antigen specificIgG3 response as compared to the mice treated with vehicle alone.Additionally, the mice treated with both PI3K-δ inhibitor and mTORinhibitor exhibit a decrease in IgE response as compared to the micetreated with PI3K-δ inhibitor alone.

(c) Rat Collagen Induced Arthritis Model

Female Lewis rats are anesthetized and given collagen injectionsprepared and administered as described previously on day 0. On day 6,animals are anesthetized and given a second collagen injection. Calipermeasurements of normal (pre-disease) right and left ankle joints areperformed on day 9. On days 10-11, arthritis typically occurs and ratsare randomized into treatment groups. Randomization is performed afterankle joint swelling is obviously established and there is good evidenceof bilateral disease.

After an animal is selected for enrollment in the study, treatment isinitiated. Animals are given vehicle, PI3K-δ inhibitor, or PI3K-δinhibitor in combination with rapamycin. Dosing is administered on days1-6. Rats are weighed on days 1-7 following establishment of arthritisand caliper measurements of ankles taken every day. Final body weightsare taken on day 7 and animals are euthanized.

The combination treatment using a compound as provided herein andrapamycin can provide greater efficacy than treatment with PI3K-δinhibitor alone.

Certain compounds provided herein (e.g., Compounds 5, 49, and 359) weretested in the rat Collagen Induced Arthritis Model using proceduressubstantially similar to those described above, and all of the testedcompounds demonstrated EC₅₀ values of less than 50 mg/kg.

Example 275: Delayed Type Hypersensitivity Model

DTH was induced by sensitizing 60 BALB/c male mice on day 0 and day 1with a solution of 0.05% 2,4 dinitrofluorobenzene (DNFB) in a 4:1acetone/olive oil mixture. Mice were gently restrained while 20 μL ofsolution was applied to the hind foot pads of each mouse. The hind footpads of the mice were used as they represent an anatomical site that canbe easily isolated and immobilized without anesthesia. On day 5, micewere administered a single dose of vehicle, a compound provided hereinat 10, 3, 1, or 0.3 mg/kg, or dexamethasone at a dose of 5 mg/kg by oralgavage. Thirty minutes later mice were anaesthetized, and a solution of0.25% DNFB in a 4:1 acetone/olive oil solution was applied to the leftinner and outer ear surface. This application resulted in the inductionof swelling to the left ear and under these conditions, all animalsresponded to this treatment with ear swelling. A vehicle controlsolution of 4:1 acetone/olive oil was applied to the right inner andouter ear. Twenty four hours later, mice were anaesthetized, andmeasurements of the left and right ear were taken using a digitalmicrometer. The difference between the two ears was recorded as theamount of swelling induced by the challenge of DNFB. Drug treatmentgroups were compared to vehicle control to generate the percentreduction in ear swelling. Dexamethasone is routinely used as a positivecontrol as it has broad anti-inflammatory activity.

Example 276: Peptidoglycan-Polysaccharide rat Arthritic Model (a)Systemic Arthritis Model

All injections are performed under anesthesia. 60 female Lewis rats(150-170) are anesthetized by inhalation isoflurane using a small animalanesthesia machine. The animals are placed in the induction chamberuntil anesthetized by delivery of 4-5% isoflurane in O₂ and then held inthat state using a nose cone on the procedure table. Maintenance levelof isoflurane is at 1-2%. Animals are injected intraperitoneally (i.p.)with a single injection of purified PG-PS 10S Group A, D58 strain(concentration 25 μg/g of bodyweight) suspended in sterile 0.85% saline.Each animal receives a total volume of 500 microliters administered inthe lower left quadrant of the abdomen using a 1 milliliter syringe witha 23 gauge needle. Placement of the needle is critical to avoidinjecting the PG-PS 10S into either the stomach or caecum. Animals areunder continuous observation until fully recovered from anesthesia andmoving about the cage. An acute response of a sharp increase in anklemeasurement, typically 20% above baseline measurement can peak in 3-5days post injection. Treatment with test compounds can be PO, SC, IV orIP. Rats are dosed no more than two times in a 24 hour time span.Treatment can begin on day 0 or any day after that through day 30. Theanimals are weighed on days 0, 1, 2, 3, 4, 5, 6, 7 and beginning againon day 12-30 or until the study is terminated. Paw/ankle diameter ismeasured with a digital caliper on the left and right side on day 0prior to injection and again on day 1, 2, 3, 4, 5, 6 and 7. On day 12,measurements begin again and continue on through day 30. At this time,animals can be anesthetized with isoflurane, as described above, andterminal blood samples can be obtained by tail vein draws for theevaluation of the compound blood levels, clinical chemistry orhematology parameters. Animals are them euthanized with carbon dioxideoverdose. A thoracotomy can be conducted as a means of deathverification.

(b) Monoarticular Arthritis Model

All injections are performed under anesthesia. 60 female Lewis rats(150-170) are anesthetized by inhalation isoflurane using a small animalanesthesia machine. The animals are placed in the induction chamberuntil anesthetized by delivery of 4-5% isoflurane in O₂ and then held inthat state using a nose cone on the procedure table. Maintenance levelof isoflurane is at 1-2%. Animals are injected intra-articular (i.a.)with a single injection of purified PG-PS 100P Group A, D58 strain(concentration 500 ug/mL) suspended in sterile 0.85% saline. Each ratreceives a total volume of 10 microliters administered into thetibiotalar joint space using a 1 milliliter syringe with a 27 gaugeneedle. Animals are under continuous observation until fully recoveredfrom anesthesia and moving about the cage. Animals that respond 2-3 dayslater with a sharp increase in ankle measurement, typically 20% abovebaseline measurement on the initial i.a. injection, are included in thestudy. On day 14, all responders are anesthetized again using theprocedure previously described. Animals receive an intravenous (I.V.)injection of PG-PS (concentration 250 uL/mL). Each rat receives a totalvolume of 400 microliters administered slowly into the lateral tail veinusing a 1 milliliter syringe with a 27 gauge needle. Baseline anklemeasurements are measured prior to IV injection and continue through thecourse of inflammation or out to day 10. Treatment with test compoundswill be PO, SC, IV or IP. Rats are dosed no more than two times in a 24hour time span. Treatment can begin on day 0 or any day after thatthrough day 24. The animals are weighed on days 0, 1, 2, 3, 4, 5, andbeginning again on day 14-24 or until the study is terminated. Paw/anklediameter is measured with a digital caliper on the left and right sideon day 0 prior to injection and again on day 1, 2, 3, 4, 5, andbeginning again on day 14-24 or until the study is terminated. At thistime, animals can be anesthetized with isoflurane, as described above,and terminal blood samples can be obtained by tail vein draws for theevaluation of the compound blood levels, clinical chemistry orhematology parameters. Animals are them euthanized with carbon dioxideoverdose. A thoracotomy can be conducted as a means of deathverification.

Example 277: Mice Models for Asthma

Efficacy of a compound provided herein in treating, preventing and/ormanaging asthma can be assessed using an conventional animal modelsincluding various mice models described in, for example, Nials et al.,Dis Model Mech. 1(4-5): 213-220 (2008).

(a) Acute Allergen Challenge Models

Several models are known in the art and any of such models can be used.Although various allergens can be used to induce asthma-like conditions,the principle is consistent throughout the methods. Briefly, asthma-likeconditions are induced through multiple systemic administration of theallergen (e.g., ova, house dust mite extracts and cockroach extracts) inthe presence of an adjuvant such as aluminum hydroxide. Alternatively,an adjuvant-free system can be used, but it usually requires a highernumber of exposures to achieve suitable sensitization. Once induced,animals exhibit many key features of clinical asthma such as: elevatedlevels of IgE; airway inflammation; goblet cell hyperplasia; epithelialhypertrophy; AHR ro specific stimuli; and early and late phasebronchoconstriction. Potential efficacy of a compound thus can beassessed by determining whether one or more of these clinical featuresare reversed or mitigated.

(b) Chronic Allergen Challenge Models

Chronic allergen challenge models aim to reproduce more of the featuresof the clinical asthma, such as airway remodeling and persistent AHR,than acute challenge models. While allergens similar to those used inacute allergen challenge models can be used, in chronic allergenchallenge models, animals are subjected to repeated exposure of theairways to low levels of allergen for a period of up to 12 weeks. Onceinduced, animals exhibit key features of human asthma such as:allergen-dependent sensitization; a Th2-dependent allergic inflammationcharacterized by eosinophillic influx into the airway mucosa; AHR; andairway remodeling as evidenced by goblet cell hyperplasia, epithelialhypertrophy, subepithelial or peribronchiolar fibrosis. Potentialefficacy of a compound thus can be assessed by determining whether oneor more of these clinical features are reversed or mitigated.

Example 278: Models for Psoriasis

Efficacy of a compound provided herein in treating, preventing and/ormanaging psoriasis can be assessed using an conventional animal modelsincluding various animal models described in, for example, Boehncke etal., Clinics in Dermatology, 25: 596-605 (2007).

As an example, the mouse model based on adoptive transfer ofCD4+CD45RB^(hi) T cells described in Hong et al., J. Immunol., 162:7480-7491 (1999) can be made. Briefly, female BALB/cBY (donor) andC.B.-17/Prkdc scid/scid (recipient) mice are housed in a specificpathogen-free environment and are used between 6 and 8 weeks of age.CD4⁺ T cells are enriched from BALB/cBy splenocytes using a mouse CD4enrichment kit. The cells are then labeled with PE-conjugated anti-CD4,FITC-conjugated anti-CD45RB, and APC-conjugated anti-CD25 antibodies.Cells are sorted using a cell sorter. CD4+CD45RB^(hi)CD25 cells arecollected. Cells are resuspended in saline and 4×10⁸ cells/mouse areinjected i.p. into C.B.-17/Prkdc scid/scid mice. Mice may be dosed withLPS, cytokines, or antibodies as necessary. Mice are monitored forexternal signs of skin lesions twice each week. After the termination,ear, back skin, lymph nodes and spleen may be collected for further exvivo studies.

Example 279: Models for Scleroderma

A compound's efficacy in treating scleroderma can be tested using animalmodels. An exemplary animal model is a mouse model for sclerodermainduced by repeated local injections of bleomycin (“BLM”) described, forexample, in Yamamoto et al., J Invest Dermatol 112: 456-462 (1999), theentirety of which is incorporated herein by reference. This mouse modelprovides dermal sclerosis that closely resembles systemic sclerosis bothhistologically and biochemically. The sclerotic changes observed in themodel include, but are not limited to: thickened and homogenous collagenbundles and cellular filtrates; gradual increase in number of mastcells; degranulation of mast cells; elevated histamine release; increasein hydroxyproline in skin; presence of anti-nuclear antibody in serum;and strong expression of transforming growth factor β-2 mRNA. Therefore,efficacy of a compound in treating scleroderma can be assessed bymonitoring the lessening of one or more of these changes.

Briefly, the following exemplary procedures can be used to generate themouse model for scleroderma: Specific pathogen-free, female BALB/C miceand C3H mice of 6 weeks old, weighing about 20 g, are purchased andmaintained with food and water ad libitum. BLM is dissolved in PBS atdiffering concentrations and sterilized with filtration. Aliquots ofeach concentration of BLM or PBS are injected subcutaneously into theshaved back of the mice daily for 1-4 weeks with a needle.Alternatively, mice are injected every other day.

Histolopathological and biochemical changes induced can be assessedusing any methods commonly practiced in the field. For example,histopathological changes can be assessed using a standardavidine-biotin peroxidase technique with anti-L3T4 monoclonal antibody,anti-Lyt2 monoclonal antibody, anti-mouse pan-tissue-fixed macrophageantibody, anti-stem cell factor monoclonal antibody, anti-transforminggrowth factor-polyclonal antibody, and anti-decorin antibody. Cytokineexpression of cellular infiltrates can be assessed by using severalanti-cytokine antibodies. Hydroxyproline level can be assessed byhydrolyzing skin pieces with hydrochloric acid, neutralizing with sodiumhydroxide, and colorimetrically assessing the hydrolates at 560 nm withp-dimethylaminobenzaldehyde. Pepsin-resistant collagen can be assessedby treating collagen sample extracted from biopsied tissues andanalyzing by polyacrylamide stacking gel electrophoresis. Mast cells canbe identified by toluidine blue, and cells containing matachromaticgranules can be counted under high magnification of a light microscope.Serum levels of various cytokines can be assessed by enzyme-linkedimmunosorbent assay, and mRNA levels of the cytokines can be assessed byreverse-transcriptase polymerase chain reaction. Autoantibodies in serumcan be detected using 3T3 fibroblasts as the substrate for thescreening.

Example 280: Models for Myositis

A compound's efficacy in treating myositis (e.g., dermatomyositis) canbe tested using animal models known in the art. One such example is thefamilial canine dermatomyositis model described in Hargis et al., AJP120(2): 323-325 (1985). Another example is the rabbit myosin inducedmouse model described in Phyanagi et al., Arthritis & Rheumatism,60(10): 3118-3127 (2009).

Briefly, 5-week old male SJL/J mice are used. Purified myosin fromrabbit skeletal muscle (6.6 mg/ml) is emulsified with an equal amount ofFreund's complete adjuvant and 3.3 mg/ml Mycobacterium butyricum. Themice are immunized repeatedly with emulsified rabbit myosin. Oncemyositis is induced, inflammatory cell filtration and necrotic musclefiber should be evident in the model. In the muscles of animals, CD4⁺ Tcells are mainly located in the perimysum and CD8⁺ T cells are mainlylocated in the endomysium and surround non-necrotic muscle fibers. TNFα,IFNγ and perforin are up-regulated and intercellular adhesion molecule 1is increased in the muscles.

To assess the efficacy of a compound, following administration of thecompound through adequate route at specified dose, the mice are killedand muscle tissues are harvested. The muscle tissue is immediatelyfrozen in chilled isopentane precooled in liquid nitrogen, and thencryostat sections are prepared. The sections are stained withhematoxylin and eosin for counting of number of infiltrated cells. Threesections from each mouse are prepared and photomicrographs are obtained.For immunohistochemical tests, cryostat sections of muscle are dried andfixed in cold acetone at −20° C. The slides are rehydrated in PBS, andthen endogeneous peroxide activity is blocked by incubation in 1%hydrogen peroxide. The sections are incubated overnight with ratanti-mouse CD4 monoclonal antibody, rat anti-mouse CD8 monoclonalantibody, rat anti-mouse F4/80 monoclonal antibody or normal rat IgG inantibody diluent. The samples are washed with PBS and incubated withbiotin-conjugated rabbit anti-rat IgG pretreated with 5% normal mouseserum. After washing with PBS, the samples are incubated withstreptavidin-horseradish peroxidase. After washing PBS, diaminobenzidineis used for visualization.

Example 281: Models for Sjögren Syndrome

A compound's efficacy in treating Sjögren's syndrome can be tested usinganimal models known in the art, for example, those described in Chioriniet al., Journal of Autoimmunity 33: 190-196 (2009). Examples include:mouse model spontaneously developed in first filial generation of NZBmice crossed to NZW mice (see, e.g., Jonsson et al., Clin ImmunolImmunopathol 42: 93-101 (1987); mouse model induced by i.p. injection ofincomplete Freund's adjuvant (id.; Deshmukh et al., J Oral Pathol Med38: 42-27 (2009)); NOD mouse models wherein Sjögren's phenotype isdeveloped by specific genotypes (see, e.g., Cha et al., Arthritis Rheum46: 1390-1398 (2002); Kong et al., Clin Exp Rheumatol 16: 675-681(1998); Podolin et al., J Exp Med 178: 793-803 (1993); and Rasooly etal., Clin Immunol Immunopathol 81: 287-292 (1996)); mouse modeldeveloped in spontaneous lpr mutation; mouse model developed in Id3knock-out mice (see, e.g., Li et al., Immunity 21: 551-560 (2004));mouse model developed in PI3K knock-out mice (see, e.g., Oak et al.,Proc Natl Acad Sci USA 103: 16882-16887 (2006)); mouse model developedin BAFF over-expressing transgenic mice (see, e.g., Groom et al., J ClinInvest 109: 59-68 (2002)); mouse model induced by injection of Roantigen into BALB/c mice (see, e.g., Oh-Hora et al., Nat. Immunol 9:432-443 (2008)); mouse model induced by injection of carbonic anhydraseII (see, e.g., Nishimori et al., J Immunol 154: 4865-4873 (1995); mousemodel developed in IL-14 over-expressing transgenic mice (see, e.g.,Shen et al., J Immunol 177: 5676-5686 (2006)); and mouse model developedin IL-12 expressing transgenic mice (see, e.g., McGrath-Morrow et al.,Am J Physiol Lung Cell Mol Physiol 291: L837-846 (2006)).

Example 282: Models for Immune Complex Mediated Disease

The Arthus reaction is a type 3 immune response to immune complexes, andthus, can be a mechanistic model supporting therapeutic hypothesis forimmune complex mediated diseases such as rheumatoid arthritis, lupus andother autoimmune diseases. For example, PI3Kγ and δ deficient mice canbe used as experimental models of the Arthus reaction and provideassessment of therapeutic potential of a compound as to the treatment ofimmune complex mediated diseases. The Arthus reaction can be inducedusing the following exemplary procedures as described in Konrad et al.,Journal of Biological Chemistry (2008 283(48): 33296-33303.

PI3Kγ- and PI3Kδ-deficient mice are maintained under dry barrierconditions. Mice are anesthetized with ketamine and xylazine, and thetrachea is cannulated. Appropriate amount of protein G-purified anti-OVAIgG Ab is applied, and appropriate amount of OVA antigen is givenintravenously. For PI3K blocking experiments, wortmanin is givenintratracheally together with the application of anti-OVA igG. Mice arekilled at 2-4 hours after initiation of inflammation, and desired followup assessments can be performed using methods known in the art.

Example 283: Isoform-Selective Cellular Assays (a) PI3Kδ Selective Assay

A compound's ability in selectively inhibiting PI3Kδ can be assessedusing RAJI cells, i.e., B lymphocyte cells derived from lymphomapatients. Briefly, serum-starved RAJI cells are stimulated withanti-human IgM, thereby causing signaling through the B-cell receptors,as described in, for example, He et al., Leukemia Research (2009) 33:798-802. B-cell receptor signaling is important for the activation,differentiation, and survival of B cells and certain B-cell derivedcancers. Reduction of phospho-AKT is indicative of compounds that mayinhibit B-cell proliferation and function in certain diseases. Bymonitoring the reduction of phospho-AKT in stimulated RAJI cells (usingfor example, phospho-AKT antibodies), a compound's potential efficacy inselectively inhibiting PI3Kδ can be assessed.

Certain compounds provided herein (e.g., Compounds 5, 49, 104, 138, 157,191, 241, 242, 270, 273, 279, 285, 288, 291, 312, 316, 326, 327, 328,329, 333, 334, 335, 336, 337, 338, 353, 354, 356, 359, 378, 379, 382,383, 387, 389, 391, 393, 394, 396, 397, 399, 401, 402, 403, 408, 410,412, 413, 414, 415, 416, 417, 418, 419, 422, 424, 425, and 428) weretested in RAJI cell model using procedures as described above. It wasfound that IC₅₀ values for phospho-AKT are as follows: Compounds 5, 49,104, 138, 157, 191, 241, 242, 270, 273, 279, 285, 288, 291, 312, 316,326, 327, 328, 329, 333, 334, 335, 336, 337, 338, 353, 354, 356, 359,378, 379, 382, 383, 387, 389, 391, 393, 394, 396, 397, 399, 401, 402,403, 408, 410, 412, 413, 414, 415, 416, 417, 418, 419, 422, 424, 425,and 428 in the range of less than 100 nM.

(b) PI3Kγ Selective Assay

A compound's ability in selectively inhibiting PI3Kγ can be assessedusing RAW264.7 macrophages. Briefly, serum-starved PAW264.7 cells arestimulated with a known GPCR agonist C5a. (See, e.g., Camps et al.,Nature Medicine (2005) 11(9): 936-943). Cells can be treated with testcompounds prior to, simultaneously with, or subsequent to thestimulation by C5a. RAW 264.7 cells respond to the complement componentfragment C5a through activation of the C5a receptor, and the C5areceptor activates macrophages and induces cell migration. Testcompounds' ability to inhibit C5a-mediated AKT phosphorylation isindicative of selective inhibition of PI3Kγ. Thus, by monitoring thereduction of phospho-AKT in stimulated RAW 264.7 cells (using forexample, phospho-AKT antibodies), a compound's potential efficacy inselectively inhibiting PI3Kγ can be assessed.

Certain compounds provided herein (e.g., Compounds 5, 49, 104, 127, 138,157, 191, 241, 242, 270, 273, 276, 279, 285, 288, 291, 312, 316, 326,327, 328, 329, 333, 334, 335, 336, 337, 338, 353, 354, 356, 359, 378,379, 382, 383, 387, 389, 391, 393, 394, 396, 397, 399, 401, 402, 403,408, 410, 412, 413, 414, 415, 416, 417, 418, 419, 422, 424, 425, and428) were tested in RAW 264.7 cell model using procedures as describedabove. It was found that IC₅₀ values for phospho-AKT are as follows:Compounds 5, 49, 127, 138, 157, 241, 270, 276, 279, 285, 288, 291, 316,379, 382, 383, 394, 397, 399, 403, 408, 410, 412, 413, 414, 415, 416,417, 418, 419, 422, and 428 in the range of less than 100 nM; Compounds104, 242, 273, 312, 326, 327, 328, 329, 335, 356, 378, 387, 389, 391,393, 396, 401, 424, and 425 in the range of between 100 nM and 1 μM;Compounds 191, 333, 334, 336, 337, 338, 353, 354, 359, and 402 in therange of between 1 M and 10 μM.

(c) PI3Kα Selective Assay

A compound's ability in selectively inhibiting PI3Kα can be assessedusing SKOV-3 cells, i.e., human ovarian carcinoma cell line. Briefly,SKOV-3 cells, in which mutant PI3Kα is constitutively active, can betreated with test compounds. Test compounds' ability to inhibit AKTphosphorylation in SKOV-3 cells, therefore, is indicative of selectiveinhibition of PI3K. Thus, by monitoring the reduction of phospho-AKT inSKOV-3 cells (using for example, phospho-AKT antibodies), a compound'spotential efficacy in selectively inhibiting PI3Kα can be assessed.

Certain compounds provided herein (e.g., Compounds 5, 49, 138, 326, 328,354, 359, 389, and 391) were tested in SKOV-3 cell model usingprocedures as described above. It was found that IC₅₀ values forphospho-AKT are as follows: Compounds 138 and 328 in the range ofbetween 100 nM and 1 μM; Compounds 5, 49, 326, 359, and 389 in the rangeof between 1 M and 10 μM; and Compounds 354 and 391 in the range ofgreater than 10 μM.

(d) PI3Kβ Selective Assay

A compound's ability in selectively inhibiting PI3Kβ can be assessedusing 786-O cells, i.e., human kidney carcinoma cell line. Briefly,786-O cells, in which PI3Kβ is constitutively active, can be treatedwith test compounds. Test compounds' ability to inhibit AKTphosphorylation in 786-O cells, therefore, is indicative of selectiveinhibition of PI3Kβ. Thus, by monitoring the reduction of phospho-AKT in786-O cells (using for example, phospho-AKT antibodies), a compound'spotential efficacy in selectively inhibiting PI3Kβ can be assessed.

Certain compounds provided herein (e.g., Compounds 5, 49, 138, 326, 328,354, 359, 389, and 391) were tested in 786-O cell model using proceduresas described above. It was found that IC₅₀ values for phospho-AKT are asfollows: Compounds 326 and 359 in the range of between 100 nM and 1 μM;Compounds 49, 138, 328, 354, and 389 in the range of between 1 M and 10μM; and Compounds 5 and 391 in the range of greater than 10 μM.

1-38. (canceled)
 39. A process for preparing Compound 49 of the formula:

or a pharmaceutically acceptable salt thereof, comprising reactingCompound 8 of the formula:

with (2-methoxypyridin-4-yl)boronic acid of the formula:

or a pinacol ester thereof.
 40. The process of claim 39, comprisingreacting Compound 8 with (2-methoxypyridin-4-yl)boronic acid.
 41. Theprocess of claim 39, wherein the reaction between Compound 8 and(2-methoxypyridin-4-yl)boronic acid, or a pinacol ester thereof, occursin the presence of PdCl₂(dppf).
 42. The process of claim 39, whereinCompound 8 is prepared by a process comprising reacting Compound 1 ofthe formula:

with 2-amino-4-chloropyrimidine-5-carbonitrile of the formula:


43. The process of claim 42, wherein the reaction between Compound 1 and2-amino-4-chloropyrimidine-5-carbonitrile occurs in the presence oftriethylamine.
 44. The process of claim 42, wherein the reaction betweenCompound 1 and 2-amino-4-chloropyrimidine-5-carbonitrile occurs in thepresence of a solvent of n-BuOH or NMP.
 45. A process for preparingCompound 359 of the formula:

or a pharmaceutically acceptable salt thereof, comprising reactingCompound 329 of the formula:

with a pinacol ester of the formula:


46. The process of claim 45, wherein the reaction between Compound 329and the pinacol ester occurs in the presence of PdCl₂(Amphos)₂.
 47. Theprocess of claim 45, wherein Compound 329 is prepared by a processcomprising reacting Compound 324 of the formula

with 4-amino-6-chloropyrimidine-5-carbonitrile of the formula:


48. The process of claim 47, wherein the reaction between Compound 324and 4-amino-6-chloropyrimidine-5-carbonitrile occurs in the presence ofHunig's base.
 49. The process of claim 47, wherein the reaction betweenCompound 324 and 4-amino-6-chloropyrimidine-5-carbonitrile occurs in thepresence of a solvent of n-BuOH.
 50. A method for inhibiting at leastone of PI3K-δ and PI3K-γ, comprising contacting a cell expressing atleast one of PI3K-δ and PI3K-γ with an effective amount of Compound 49or Compound 359 of the formula:

or a pharmaceutically acceptable salt thereof.
 51. The method of claim50, wherein the cell is contacted in vitro.
 52. The method of claim 50,wherein the cell is contacted ex vivo.
 53. The method of claim 50,wherein a live cell is contacted.
 54. The method of claim 53, whereinthe cell is a T-cell.
 55. The method of claim 54, wherein the cell is aT-cell from a patient suffering from a hematological cancer.
 56. Themethod of claim 55, wherein the hematological cancer is acutelymphocytic leukemia, hairy cell leukemia, myelodysplasia,myeloproliferative disorders, NK cell leukemia, acute myelogenousleukemia (AML), chronic myelogenous leukemia (CML), mastocytosis,chronic lymphocytic leukemia (CLL), multiple myeloma (MM),myelodysplastic syndrome (MDS), diffuse large B-cell lymphoma, B-cellimmunoblastic lymphoma, NK cell lymphoma, small non-cleaved celllymphoma, Kaposi's Sarcoma, viral-induced cancers, human lymphotropicvirus-type 1 (HTLV-1) leukemia/lymphoma, adult T-cell leukemia/lymphoma,Hodgkin disease, non-Hodgkin lymphoma, mantle cell lymphoma, or T-celllymphoma.
 57. The method of claim 56, wherein the hematological canceris non-Hodgkin lymphoma.
 58. The method of claim 56, wherein thehematological cancer is multiple myeloma.